U.S. patent number 11,179,328 [Application Number 16/747,070] was granted by the patent office on 2021-11-23 for compositions and methods for the treatment of presbyopia.
This patent grant is currently assigned to LENZ THERAPEUTICS, INC.. The grantee listed for this patent is LENZ Therapeutics, Inc.. Invention is credited to Gerald Horn.
United States Patent |
11,179,328 |
Horn |
November 23, 2021 |
Compositions and methods for the treatment of presbyopia
Abstract
The invention provides compositions and methods for the
treatment of presbyopia. The compositions preferably comprise
aceclidine. The compositions optionally contain a surfactant and a
viscosity agent.
Inventors: |
Horn; Gerald (Deerfield,
IL) |
Applicant: |
Name |
City |
State |
Country |
Type |
LENZ Therapeutics, Inc. |
Rancho Santa Fe |
CA |
US |
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Assignee: |
LENZ THERAPEUTICS, INC. (Rancho
Santa Fe, CA)
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Family
ID: |
1000005952656 |
Appl.
No.: |
16/747,070 |
Filed: |
January 20, 2020 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20200146976 A1 |
May 14, 2020 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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16106730 |
Aug 21, 2018 |
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15956936 |
Apr 19, 2018 |
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15864703 |
Jan 8, 2018 |
10617763 |
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15235431 |
Aug 21, 2018 |
10052313 |
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15073139 |
Dec 5, 2017 |
9833441 |
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15073089 |
Dec 19, 2017 |
9844537 |
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14742903 |
Apr 26, 2016 |
9320709 |
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14223639 |
Dec 5, 2017 |
9089562 |
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61938438 |
Feb 11, 2014 |
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61917620 |
Dec 18, 2013 |
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61904510 |
Nov 15, 2013 |
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61882998 |
Sep 26, 2013 |
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61871215 |
Aug 28, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
9/0048 (20130101); A61K 47/10 (20130101); A61K
45/06 (20130101); A61K 47/26 (20130101); A61K
31/439 (20130101); A61K 47/02 (20130101); A61P
27/10 (20180101); A61K 47/34 (20130101); A61K
47/32 (20130101); A61K 31/4409 (20130101); A61K
9/08 (20130101); A61K 47/38 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61K 45/06 (20060101); A61K
47/10 (20170101); A61K 47/34 (20170101); A61K
47/32 (20060101); A61K 31/4409 (20060101); A61P
27/10 (20060101); A61K 31/439 (20060101); A61K
47/38 (20060101); A61K 47/26 (20060101); A61K
47/02 (20060101); A61K 9/08 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Glaucostat Josefa Valcarecel Glaucostat.RTM. 2% colirio. cited by
examiner .
Romano. Brit. Jr. Ophthal. (I970) 54, 5 10 Double Blind cross-over
comparison of aceclidine and pilocarpine in open-angle glaucoma
(Year: 1970). cited by examiner .
Kaufman PL, Lutjen Drecoll E, Croft MA. Presbyopia and glaucoma:
two diseases, one pathophysiology? The 2017 Friedenwald Lecture.
Invest Ophthalmol Vis Sci. 2019;60:1801-1812. (Year: 2019). cited
by examiner.
|
Primary Examiner: Blanchard; David J
Assistant Examiner: Chickos; Sarah J
Attorney, Agent or Firm: Wood, Phillips, Katz, Clark &
Mortimer
Claims
What is claimed is:
1. A method of treating presbyopia comprising administering to a
subject in need thereof an ophthalmological composition comprising
aceclidine as the only active agent.
2. A method of treating presbyopia comprising administering to a
subject in need thereof an ophthalmological composition comprising
aceclidine as the only active agent and a viscosity agent.
3. A method of treating presbyopia comprising administering a
composition comprising aceclidine as the only active agent and one
or more nonionic surfactants to a subject in need thereof.
4. The method of claim 3, wherein aceclidine is at a concentration
from about 0.25% to about 2.5% w/v, wherein w/v denotes weight by
total volume of the composition.
5. The method of claim 3, wherein aceclidine is at a concentration
from about 0.75% to about 2.5% w/v.
6. A method of treating low regular astigmatism, low or high
irregular astigmatism, keratoconic ectasia, night vision
halos/starbursts, night vision reduced contrast, and low myopia, or
hyperopia, with or without astigmatism, comprising administering to
a subject in need thereof an ophthalmological composition
comprising aceclidine as the only active agent and a viscosity
agent.
Description
BACKGROUND OF THE INVENTION
As a person ages the minimum distance from the eye at which an
object will come into focus, provided distance vision is corrected
or is excellent unaided, increases. For example, a 10-year-old can
focus on an object or a "focal point" only three inches (0.072
meters) from their eye while still retaining excellent distance
vision; a 40-year-old at six inches (0.15 meters); and a
60-year-old at an inconvenient 39 inches (1.0 meter). This
condition of increasing minimum focal length in individuals with
excellent unaided distance vision is called presbyopia, loosely
translated as "old-man eye".
Excellent unaided distance vision is also known as emmetropia. The
inability to focus on distant focal points is known as myopia and
the inability to focus on near focal points is known as hyperopia.
Specifically, "distance" vision is considered any focal point 1
meter or more from the eye and near vision is any focal point less
than 1 meter from the eye. The minimum focal length at which an
object will come into focus is known as the "near point". The
change in focus from distance to the near point and any focal point
in between is called accommodation. Accommodation is often measured
in diopters. Diopters are calculated by taking the reciprocal of
the focal length (in meters). For example, the decrease in
accommodation from a 10-year-old eye to a 60-year-old eye is about
13 diopters (1/0.072 meters=13.89 diopters; 1/1 meter=1
diopter).
The highest incidence of first complaint of presbyopia occurs in
people ages 42-44. Presbyopia occurs because as a person ages the
eye's accommodative ability which uses near reflex-pupil
constriction, convergence of the eyes and particularly ciliary
muscle contraction, decreases. This reduction in accommodation
results in an inadequate change in the normal thickening and
increased curvature of the anterior surface of the lens that is
necessary for the shift in focus from distant objects to near
objects. Important near focus tasks affected by presbyopia include
viewing computer screens (21 inches) and reading print (16
inches).
Presbyopia is a normal and inevitable effect of ageing and is the
first unmistakable sign for many in their forties that they are
getting older. One study found that more than 1 billion people
worldwide were presbyopic in 2005. This same study predicted that
number to almost double by the year 2050. If everyone over the age
of 45 is considered to be presbyopic, then an estimated 122 million
people in the United States alone had presbyopia in 2010. As baby
boomers reach the critical age, this number is only going to
increase.
Presbyopia carries with it a stigma resulting from the limitation
in ability to quickly function at many tasks requiring focusing at
both distant and near points, which once occurred almost
immediately. In the presbyopic patient, these tasks can be
performed only by the use of eyeglasses, contact lenses or after
undergoing invasive surgery. One such optical modification, the
monovision procedure, can be executed with the use of glasses,
contact lenses or even surgery. The monovision procedure corrects
one eye for near focus and the other eye for distance focus.
However, monovision correction is normally accompanied by loss of
depth perception and distance vision particularly in dim light
(e.g. night). Other surgical procedures that have been developed to
relieve presbyopia include: (1) the implantation of intraocular
lenses (INTRACOR.RTM.; registered trademark of Technolas Perfect
Vision GMBH); (2) reshaping of the cornea (PresbyLASIK and
conductive keratoplasty); (3) scleral band expansion; and (4)
implantation of corneal inlays (Flexivue Microlens; registered
trademark of PresbiBio LLC, Kamra.RTM.; registered trademark of
AcuFocus, Inc. and Vue+). Kamra.RTM. corneal inlays manufactured by
AcuFocus work by inlaying a pinhole on the cornea to increase the
depth of focus.
A similar effect can be achieved with general miotic agents, such
as pilocarpine (a non-selective muscarinic acetylcholine receptor
agonist), carbachol (a non-selective muscarinic acetylcholine
receptor agonist), and phospholine iodide (an acetylcholinesterase
inhibitor). These general miotics can induce a pinhole pupil at
sufficient concentrations to achieve pupils below 2.0 mm and
potentially extend depth of focus much like an inlay, but at
concentrations sufficient to cause pinhole pupil diameters of 2.0
mm or less these agents trigger increased ciliary muscle
contraction and induce accommodation of any remaining reserves,
improving near vision at the expense of distance vision in
individuals who still retain some accommodative function. The side
effects of ciliary spasm induced migraine like brow pain and
blurred distance vision from induced myopia beyond the ability of a
pinhole pupil to correct then necessitate using weaker
concentrations with much shorter acting and more marginal effect,
such as found with pilocarpine. In such cases even slight hyperopia
helps offset the induced myopia while even very small increments of
myopia, which is very common, exacerbate it. In extreme cases, such
ciliary muscle spasms may possibly be associated with anterior
chamber shallowing and pull on the ora serrata of the retina,
resulting in a retinal tear and or retinal detachment.
Miotic agents have been described in various patent and patent
applications for the treatment of presbyopia. U.S. Pat. Nos.
6,291,466 and 6,410,544 describe the use of pilocarpine to regulate
the contraction of ciliary muscles to restore the eye to its
resting state and potentially restore its accommodative
abilities.
U.S. Pat. No. 8,524,758 describes the use of pilocarpine with the
non-steroidal anti-inflammatory, diclofenac, to reduce brow ache
from ciliary spasm and increase the time in which the ciliary
muscle contraction is regulated. International PCT Application
Publication WO/2013/041967 describes the use of pilocarpine with
oxymetazoline or meloxicam to temporarily overcome ocular
conditions such as presbyopia.
U.S. Pat. No. 8,299,079 (HEK Development LLC) describes the use of
direct acting general miotic agents such as pilocarpine, carbachol
and phospholine iodide with the alpha 2 selective vasoconstrictor
brimonidine at a concentration from 0.05% to 3.0% w/v. However, the
use of brimonidine concentrations of about 0.20% (or any at or
above 0.05%) w/v induces ciliary spasm with often migraine
intensity brow and/or headaches, and frequently results in
increased rebound hyperemia. For example, rebound redness occurs in
25% of patients using brimonidine 0.20% w/v (Alphagan.RTM.,
registered trademark of Allergan, Inc.) twice daily.
US Patent Application Publication No. 2014/0113946 describes the
use of pilocarpine with the alpha 1 and mild alpha 2 agonist
vasoconstrictor oxymetazoline, demonstrating limitations in
distance sharpness and duration, whereby a cohort largely
restricted to mild hyperopes is required to neutralize the induced
myopia (Table 5). Of the 16 eyes treated only three were -0.25 to
-0.50 diopters, and eight were mildly hyperopic. Of the -0.50
diopter eyes two were reduced to 20.40 distance. Further, duration
was limited as full effect became diminished in about four hours.
Pupil size range was from 2.0 mm to 2.7 mm, where enhanced near
effect and distance sharpness from depth of focus was minimal to
absent.
These attempts at miotic treatment for presbyopia all induce
transient myopia of several diopters reducing distance vision to
about legal blindness or worse at the expense of improved near
vision for the full duration of their action, typically lasting
several hours. This myopic effect is amplified by the exponential
drop off in distance acuity with even small increments of nominal
myopia in terms of unaided untreated vision. For example, a person
having mild myopia (e.g. spherical equivalents of -0.25 D, -0.50 D)
that is usually associated with glasses free distance vision,
typically will have several lines of distance vision loss after
instillation of pilocarpine 1% (i.e. spherical equivalent of -0.75
D.).
Miotics historically used to treat glaucoma, other than
pilocarpine, particularly aceclidine, are also associated with
ciliary spasm, brow and/or headache, and myopic blur. Further,
aceclidine is unstable in solution. Normally, aceclidine is stored
in a two-bottle system; one bottle containing the lyophilized
aceclidine and the second bottle containing the diluent necessary
to reconstitute the lyophilized aceclidine before topical
instillation. However, the primary issue with its use as a
presbyopic miotic is the attendant pain and in some cases distance
blur that may be induced.
U.S. Pat. No. 9,089,562 describes a composition containing
aceclidine combined with a cycloplegic agent, such that in
preferred embodiments aceclidine 1.45% is combined with tropicamide
0.042%. The addition of the cycloplegic agent at extremely low
concentrations (less than 0.10%) surprisingly still results in
pupil miosis and allows for useful distance and improved near
vision without ciliary spasm (often a migraine like brow ache that
can be extremely painful and disabling), which is induced by the
use of aceclidine alone. Further, aceclidine and the cycloplegic
agent require particular narrowly defined ratios and ranges of
concentrations relative to each other such that complications in
the manufacturing and regulatory process, particularly the need for
lyophilization of aceclidine to allow its stable storage, and
attendant effects of cryoprotectant/lyoprotectant (hereinafter
referred to as "cryoprotectant") required, where it is a discovery
of the present invention the addition of a cryoprotectant such as a
polyol, in a preferred embodiment mannitol, results in reduced
efficacy of the defined ranges and ratios of concentrations of U.S.
Pat. No. 9,089,562. Due to these medical and practical
inefficiencies, it is discovered an aceclidine composition
requiring same or slightly higher concentrations of aceclidine and
much lower concentrations than U.S. Pat. No. 9,089,562 or in some
cases no cycloplegic agent, while allowing for formulation
modifications to lyophilize aceclidine would be preferred for the
treatment of presbyopia with necessary commercially stable
formulations. However, to date, no aceclidine composition with
amounts of cycloplegic agent lower than that claimed in U.S. Pat.
No. 9,089,562 has been effective to treat presbyopia because, as
mentioned above, aceclidine alone, particularly young and
middle-aged presbyopes (ages 45 to 58), severe ciliary spasms and
may cause accommodative induced distance blur in some subjects.
Thus, there is a need in the art for a treatment of presbyopia that
is non-invasive and convenient with minimal side effects.
Specifically, there is a need for an ophthalmological composition
that will allow a person suffering from presbyopia to focus on near
objects without significant side effects such as diminished
distance vision, blurred vision, pain, redness, impaired night
driving or incapacitating dim light vision, induced nasal
congestion, or risk of retinal detachment. Further, there is a need
in the art for a reduction or elimination of the need for a
cycloplegic agent to be used with aceclidine potentially enhancing
duration and efficacy, as well as for means of storage of stable
aceclidine compositions, where such compositions preferably enhance
both distance and near depth of focus allowing pupil miosis to a
1.50 to 2.0 mm range without clinically significant side
effects.
SUMMARY OF THE INVENTION
In certain embodiments, the present invention is directed to
compositions and methods for the treatment of presbyopia.
In certain embodiments, the present invention is directed to
compositions and methods for the treatment of presbyopia comprising
a muscarinic agonist, wherein the muscarinic agonist preferentially
activates M1 and M3 muscarinic acetylcholine receptors. In still
more preferred embodiments the muscarinic agonist is more highly
selective for M1 than M3. In certain embodiments, the present
invention is directed to compositions and methods for the treatment
of presbyopia comprising a muscarinic agonist that preferentially
activates M1 and M3 muscarinic acetylcholine receptors.
In certain embodiments, the present invention is directed to
compositions and methods for the treatment of presbyopia comprising
a muscarinic agonist selected from the group consisting of
aceclidine, talsaclidine, vedaclidine, sabcomeline, cevimeline,
WAY-132983, AFB267B (NGX267), AC-42, AC-260584, 77-LH-28-1, and
LY593039 or any pharmaceutically acceptable salts, esters,
analogues, prodrugs or derivatives thereof.
In certain embodiments, the present invention is directed to
compositions and methods for the treatment of presbyopia comprising
a muscarinic agonist that activates only M1 muscarinic
acetylcholine receptors.
In certain other embodiments, the present invention is directed to
an ophthalmological composition for the treatment of presbyopia
comprising aceclidine, preferably at a concentration from about
0.25% to about 2.5% w/v, more preferably from about 0.75% to about
2.5% w/v.
In certain preferred embodiments, the ophthalmological compositions
of the present invention further comprise sodium chloride.
In certain preferred embodiments, the present invention is directed
to ophthalmological compositions for the treatment of presbyopia
comprising aceclidine, one or more nonionic surfactants and a
viscosity agent.
In certain preferred embodiments, the one or more nonionic
surfactants of the present invention are selected from the group
consisting of a polysorbate, tyloxapol, a poloxamer, a
cyclodextrin, vitamin E TPGS and a polyoxyl castor oil, a polyoxyl
stearate, polyethylene glycol alkyl ether and
2-[[10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,11,12,14,15,1-
6,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]ethanol, more
preferably a polysorbate and/or a cyclodextrin and even more
preferably polysorbate 80, poloxamer 407 and/or poloxamer 188,
preferably at a total concentration from about 2% to about 7%
w/v.
In certain preferred embodiments, the viscosity agent provides a
viscosity of the total composition of about 25 centipoise ("cps")
or more at 25.degree. C. and 0 shear, preferably from about 50 to
about 10,000 cps, more preferably from about 100 to about 5,000 cps
and most preferably from about 150 to about 450 cps.
In certain preferred embodiments, the viscosity agent is selected
from the group consisting of a cellulose derivative, hyaluronate, a
carbomer and a gum, more preferably high molecular weight
carboxymethyl cellulose, carbomer 940 and hydroxypropylmethyl
cellulose.
In certain preferred embodiments, the ophthalmological compositions
of the present invention further comprise one or more antioxidants
selected from the group consisting of ethylenediaminetetraacetic
acid (EDTA), ethylenediaminetetraacetic acid dihydrate, sodium
citrate and citrate buffer, preferably selected from the group
consisting of ethylenediaminetetraacetic acid dihydrate and sodium
citrate or citrate buffer.
In certain preferred embodiment, ophthalmological compositions of
the present invention have a pH of about 4.0 to about 8.0.
In certain other embodiments, the present invention is directed to
a method of treating presbyopia comprising administering to a
subject in need thereof a composition of the present invention.
In certain other embodiments, the present invention is directed to
a method of treating a refractive error of the eye in a subject in
need thereof comprising administering to a subject in need thereof
a pharmaceutically acceptable amount of a composition of the
present invention wherein the refractive error of the eye is
selected from presbyopia, myopia, hyperopia, astigmatism or a
combination thereof.
The present invention is directed to methods of treating low
regular astigmatism, low or high irregular astigmatism, keratoconic
ectasia, and low myopia, or hyperopia, with or without astigmatism,
comprising administering to a subject in need thereof an
ophthalmological composition of the present invention.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a graphical representation of the effects of pilocarpine
and aceclidine with or without tropicamide and with or without a
carrier on near and distance vision in a patient over the age of
45.
FIG. 2 is a graphical representation of the effects of addition of
non-ionic surfactants and viscosity agents on near vision acuity
and duration of effect. Line-Hours denotes lines improved times
duration of effect.
FIG. 3 is a graphical representation of the Efficacy Index for
formulas #L33-#L94. Box color denotes a comfort level of good for
white, fair for cross-hatched and poor for black.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to compositions and methods of
treating presbyopia, irregular astigmatism, and/or refractive
error, comprising administering to a patient in need thereof a
pharmaceutical composition comprising a muscarinic agonist that
preferentially activates M1 and M3 muscarinic acetylcholine
receptors, preferably activate M1 more than M3 and most preferably
aceclidine or its derivatives. Aceclidine has been surprisingly and
unexpectedly discovered to provide enhanced presbyopic reversal
with negligible side effects day or night (when viewing includes
one or more direct or reflected light sources).
Aceclidine is traditionally used as a treatment for glaucoma. When
aceclidine is used to treat glaucoma, it is normally stored in a
two-bottle system; one bottle containing the lyophilized aceclidine
and the second bottle containing the diluent necessary to
reconstitute the lyophilized aceclidine before topical
instillation. Romano J. H., Double-blind cross-over comparison of
aceclidine and pilocarpine in open-angle glaucoma, Brit J Ophthal,
August 1970, 54(8), 510-521. It is a further aspect of the present
invention to provide an aqueous aceclidine composition that is
stable in combination with cold chain storage. It is yet a further
aspect of the present invention to provide a method of stabilizing
aqueous aceclidine by combining effective excipients, pH ranges and
temperature ranges.
The compositions and methods of the present invention treat
presbyopia by improving depth of focus in patients with presbyopia
by administering an ophthalmological composition to the eye that
reduces pupil dilation in the dark or in dim light, produces a
particular degree and duration of miosis without accommodation,
provides cosmetic whitening and/or induce redness prophylaxis. The
compositions and methods of the present invention also do not cause
significant pupil rebound, tachyphylaxis, ciliary spasms, induction
of myopia or reduction in distance vision. Additionally, the
compositions and methods of the present invention allow for the
further improvement in visual acuity and depth perception of
binocular (both eyes) treatment. The ophthalmological composition
of the present invention surprisingly creates a pupil of from about
1.5 to about 2.4 mm at the anterior iris plane and about 2.0 mm at
the corneal surface. Not wishing to be held to particular theory
the clinical effect appears to involve both with modulated increase
in accommodative tone and enhanced pinhole near depth of focus for
improved near vision, estimated to be about -1.25 D or less, but
restricted in power to remain within the range of pinhole
correction for distance, found to be about -1.00 D or less creating
a sum increase that may in some cases create a near vision add of
+2.00 D or more without distance blur; and with a reduction or
ablation of the redness that is otherwise a hallmark of the use of
miotic agents. The pupil miosis of the present invention with such
modulation and restriction of peak accommodative tone is superior
to the pinhole effect of the Kamra.RTM. and Flexivue Microlens.RTM.
corneal inlays, allowing binocular treatment without peak dimming.
Pupil miosis of the present invention with modulated accommodation
is also superior to inlays because the constriction of the actual
pupil does not result in the attendant severe night vision
disturbance caused by the light scattering borders of the
pre-corneal pinholes created by the inlays. Further pupil miosis
provides a greater field of vision and transmission of more focused
light, and in a discovered optimal pupil range of about 1.5 mm to
2.1 mm using formulation discoveries of the present invention does
so with negligible to mild and very tolerable dimming and enhanced
contrast, distance vision, reduced glare at night, and improved
near vision.
The use of aceclidine has a minimal effect on the longitudinal
ciliary muscle, thus reducing risk of retinal detachment when
compared to the use of general muscarinic agonists such as
pilocarpine and carbachol. The further inclusion of a cycloplegic
agent resulted in only 0.04 mm of anterior chamber shallowing.
Aceclidine, particularly as enhanced for the present invention,
also has greater magnitude, duration, and control of minimum pupil
diameter than conventional pilocarpine with or without alpha
agonists, and less anterior chamber inflammation with chronic use.
Compositions of the present invention achieve these advantages by
allowing both pinhole near vision depth perception benefit and
modest accommodative increase below the threshold of induced myopic
distance blur through the miotic pupil, whereby, not wishing to be
held to particular theory, it is believed the rate of miosis and
the rate of accommodative increase maintain a synchronous balance
in preferred embodiments allowing pinhole correction of otherwise
induced accommodative blur in prior art applications of miotics for
presbyopic correction. This combination thus is found to avoid the
distance blur typically seen in patients as a response to
pilocarpine and/or carbachol induced miosis without the formulation
discoveries of the present invention, as well as the excessive
accommodative myopia and ciliary spasm manifested as brow ache or
generalized migraine-like headache.
Such conventional formulations of pilocarpine, in order to affect
any reasonable duration of effect, are still restricted to less
than or equal to about 4 hours in most cases, as the high ratio of
accommodation to pupillary miosis requires minimal concentrations
of pilocarpine of about 1.0% to minimize but not eliminate distance
induced myopic blur and ciliary spasm. Further pilocarpine must be
instilled monocularly to minimize intolerable distance blur to a
still bothersome 2-3 lines of distance blur. Even instilled
monocularly, pilocarpine still may create bothersome attendant
distance blur and must be restricted to about 1.0%. Upon
instillation of 1.0% pilocarpine pupil size is about 2.3 mm or
larger in most subjects and thereby restricts any significant
pinhole depth perception benefit as well as any pinhole filtering
of induced myopic rays. The restriction to about 1.0% for these
conventional formulations of pilocarpine with the attendant short
duration and still bothersome but reduced distance blur in
emmetropes or myopes (somewhat neutralized in low hyperopes) are
attempts to prevent extremely strong accommodation of 5D to 11 D
well known to occur at higher concentrations of pilocarpine.
Any effects on accommodation may be further reduced or totally
eliminated in preferred embodiments by combining a miotic with a
cycloplegic agent in a narrow and particular ratio of miotic to
cycloplegic, where such ratios as discovered for U.S. Pat. No.
9,089,562, such as about 35:1 for a preferred embodiment, become
greatly increased for the present invention in the presence of
cryoprotectant as to a factor of about 300%-700%. Aceclidine is
capable of producing the increased depth of focus by both pupil
miosis below 2.3 mm and modest accommodation described in the
present invention. Particularly enhanced miosis occurs with use of
compositions of the present invention. This enhanced miosis makes
it possible to use an .alpha.-2 agonist at very low concentrations
if desired to reduce mild eye redness. Other combinations of
inactive ingredients reduce or effectively eliminate induced
redness without such agonists. Further, due to the apparent and
surprisingly selective nature of aceclidine, and the commercially
stable aceclidine formulation discoveries of the present invention,
administration to the eye of compositions of the present invention
result in a net strongly enhanced near vision acuity from both
pupil miotic pinhole effect and moderate modulated ciliary
accommodation. These beneficial effects are accompanied by a
filtering pupil effect, which eliminates any distance blur from the
accommodation, correcting residual refractive error and optical
aberrations as may exist to in many cases improve distance vision
as well. Thus, the administration of aceclidine results in pupil
miosis without excessive accommodation and attendant distance
blur.
However, aceclidine alone may cause substantial redness and brow
ache in some individuals. Without formulation enhancement of the
present invention such as requiring cycloplegic agent,
cryoprotectant or both, aceclidine may produce either less than
optimal pupil miosis at low concentrations or at higher
concentrations require more than desired peak miosis to attain
satisfactory duration of greater than 3-4 hours. However the use of
a cycloplegic agent has been found to be highly sensitive to other
inactive ingredients in the formulation not usually associated with
effects on active agents, and particularly for cryoprotectants as
found to be preferred commercially for aceclidine reduce or
eliminate the need for this cycloplegic requirement to extremely
low concentrations in a preferred embodiment, rendering 0.042%
sufficiently high when a cryoprotectant is present (e.g. a polyol
such as mannitol) to cause substantial loss of efficacy. Further,
aceclidine without formulation enhancements of the present
invention causes dimming of vision in dim or absent lighting as
well as ciliary pain above a reasonably tolerable threshold that
may last for an hour or more and be similar to a severe migraine
headache.
Certain embodiments of the present invention enhance the discovered
preferred degree of pupillary miosis by providing a consistent
range of effect of about 1.50-2.20 mm for most patients using a
preferred embodiment of a nonionic surfactant and viscosity agent.
Similar benefit may be achieved using other permeation enhancers,
particularly hydroxypropylmethyl cellulose, high viscosity
carboxymethyl cellulose, Carbopol (polyacrylic acid or carbomer),
and various viscosity additives that increase drug residence time,
such as xanthan gums, guar gum, alginate, and other in situ gels
well known to experts in the art. It is well known to experts in
the art that the exact concentration of a specific viscosity agent
will depend on both the molecular weight for that agent selected
and the concentration, such that for increased molecular weight a
reduced concentration can have the same viscosity. The present
invention further prevents nasal congestion otherwise occurring
when substantial aceclidine levels reach the nasal mucosa, due to
the rheologic properties of the preferred embodiment.
The combination of aceclidine and a low concentration of a
selective .alpha.-2 adrenergic receptor agonist (.alpha.-2 agonist
or .alpha.-2 adrenergic agonist), such as fadolmidine, brimonidine
or guanfacine, allows for the desired miotic effect with diminished
or no redness. The use of low concentrations of a selective
.alpha.-2 agonist results in substantial reduction of hyperemia
with greatly reduced risk of rebound hyperemia that is found in
concentrations of about 0.06% w/v or more. Furthermore, the use of
low concentrations of selective .alpha.-2 agonist does not
adversely modify the pupil constriction caused by aceclidine. In
contrast, the use of brimonidine 0.20% w/v, when topically applied
for pupil modulation for night vision, result in tachyphylaxis of
pupil modulation due to .alpha.-2 receptor upregulation in almost
100% of treated subjects within four weeks of use.
Unexpectedly, the addition of a cycloplegic agent results in
reduction of any brow ache or associated discomfort by further
reducing the degree of ciliary spasms on topical instillation
without impairing the miotic response. More unexpectedly and
surprisingly, the ratio of 1.40% aceclidine to about 0.040%
tropicamide in a preferred embodiment of U.S. Pat. No. 9,089,562
(35:1) becomes about 1.75% aceclidine to about 0.004% to 0.010%
tropicamide (350:1, 175:1 respectively) in the presence of
mannitol, where 2.5% provides better effect than 4.0%.
The lack of impairment of the miotic response is an unexpected
surprising discovery, as particular cycloplegic agents, such as
tropicamide, have known pupil dilating effects at concentrations as
low as 0.01% w/v (Grunberger J. et al., The pupillary response test
as a method to differentiate various types of dementia,
Neuropsychiatr, 2009, 23(1), pg 57). More specifically cycloplegic
agents cause pupil mydriasis (i.e. dilation of the radial muscle of
the iris). Further, the addition of a cycloplegic agent to the
miotic agent unexpectedly increases the time at which the pupil
maintains the desired size range without becoming too restricted.
Peak miotic effect at 30-60 minutes can be titrated in inverse
relation to the cycloplegic concentration. The concentrations of
tropicamide discovered in the present invention apparently cause
more relaxation of the ciliary muscle than the iris radial
musculature. In fact, iris mydriasis is discovered to be suppressed
by the addition of tropicamide to compositions containing
concentrations of aceclidine used in the present invention, with
instead a more consistent level of miosis for the duration of the
miotic effect. Additionally, and quite surprisingly, unexpectedly,
and beneficially the addition of tropicamide can reduce the degree
of peak pupil miosis without inducing mydriasis thereby creating a
more constant and ideal pupil size throughout the drug induced
miosis. This more consistent pupil size allows for beneficial near
and distance vision without the adverse dimming or loss of
resolution due to diffraction limits at the very reduced pupil
sizes seen at peak pupil miosis (e.g. 1.25 mm).
Previously, in U.S. Pat. No. 9,089,562, it was surprisingly found
that the addition of at least 0.04% w/v cycloplegic agent resulted
in an abatement of ciliary side effects caused by the
administration of aceclidine (1.40%) to the eye, in a preferred
embodiment, but such formulations are not as constituted
sufficiently stable for commercial use, and typically have a
duration of about five to six hours maximum.
Several additional discoveries of the present invention allow for
commercially stable aceclidine formulations with enhanced efficacy
and duration:
Equally or more surprising than the synergistic effects of
cycloplegics of 0.040% added to aceclidine 1.40%, is the discovery
of the present invention that combination of aceclidine 1.50%-2.0%,
and preferably about 1.75% and a cryoprotectant, preferably a
polyol, in a preferred embodiment mannitol, particularly at 0.5% to
4.0% and most preferably about 2.5%, can achieve a similar pupil
range with reduced or absent ciliary side effects. The
cryoprotectant when combined with aceclidine can then be combined
to allow lyophilization without degradation of aceclidine and
simultaneously further reduce or eliminate the need for a
cycloplegic agent for the present invention vs. the teachings of
cycloplegic concentration ranges required in U.S. Pat. No.
9,089,562. Optionally, the addition of a cryoprotectant can
therefore also be used to greatly reduce (i.e. no more than 0.025%
w/v cycloplegic agent, preferably 0.004% to 0.015% and most
preferably 0.005% to 0.010%) the concentration of cycloplegic
required to further eliminate mild, but potentially bothersome,
ciliary side effects particularly in younger presbyopes and further
modulate pupil miosis over aceclidine and a cryoprotectant
combinations alone, reducing and in most cases eliminating any
bothersome peak concentration dimming, as found in preferred
embodiments of the present invention. In preferred embodiments it
is discovered that aceclidine about 1.50%-2.0% and more preferably
1.75% and mannitol about 0.5%-4.0% and more preferably 2.5% provide
optimal concentration combinations for the present invention, that
are necessary but not sufficient for about 3 lines of near
improvement and 5 or more hours duration desired for an effective
topical presbyopic composition, where additional formulation
discoveries can further enhance the desired clinical near
improvement magnitude and duration;
It is surprisingly discovered that adding a viscosity agent to
compositions described above only modestly improves magnitude and
duration, however when first adding a nonionic surfactant, such as
polyoxyl stearate or polysorbate 80, optimal concentrations are
discovered that provide greatly improved magnitude and duration for
the present invention, to which viscosity may then provide added
duration much more substantially than when added alone. For
polysorbate 80 or polyoxyl 40 stearate concentrations of 1.0% to
10.0%, and more preferably about 2.5% to 5.0% w/v have been found
to be beneficial.
When formulation improvements are combined, preferred embodiments
such as aceclidine 1.75%, mannitol 2.5%, and polysorbate 80 2.75%
result. Viscosity agents such as high viscosity carboxymethyl
cellulose ("CMC") are surprisingly discovered to moderately enhance
magnitude and greatly enhance duration, unlike with formulations in
a. above alone. High molecular weight CMC concentrations of 0.75%
to 1.75%, and most preferably about 1.40%, or hydroxypropylmethyl
cellulose ("HPMC") at about 0.25% to 2.0%, more preferably about
0.50% or 1.50%, and most preferably about 1.0% to 1.25%, when
combined result now in about +3 lines of near vision improvement or
greater, at a duration of 5-10 hours, at a mean of about 7 hours or
greater vs. pilocarpine 1.0% of about less than 4 hours;
Not wishing to be held to particular theory citrate in combination
with EDTA as a preferred embodiment buffer appears to 1) reduce
redness; 2) enhance sorbate preservative shelf life, and in
combination of the above with BAK 0.005% to 0.02% (0.02% preferred)
further enhances near vision lines to about 4 lines and duration to
about 8 to 12 hours.
In a preferred embodiment, compositions of the present invention
further comprise sodium chloride, preferably at a concentration
from about 0.5% to about 1.5% w/v, more preferably from about 0.65%
to about 0.9% w/v. Optionally, sodium chloride may be substituted
with boric acid, preferably at 0.35% or potassium borate,
preferably at 0.47%;
Not wishing to be held to particular theory, it appears the
addition of nonionic surfactant at optimized concentration of about
2.0% to about 7.0% enhances permeation of aceclidine into the eye,
which may relate to optimal micellar size particularly once of
micromicellar or nanomicellar range. This increased permeation
coincides with the desirable increase in magnitude and duration and
absent tropicamide but in the presence of mannitol with slight
increases in ciliary sensation and dimming. Therefore, in the
presence of the combined formulation enhancements above, where a
cycloplegic agent is no longer required, addition of a nonionic
surfactant at concentrations found to be preferred may be further
improved with much lower concentrations of a cycloplegic agent than
those found in U.S. Pat. No. 9,089,562, such as the use of about
0.042% tropicamide with aceclidine 1.40%. For the present invention
then preferred embodiments include aceclidine of about 1.75%,
mannitol 2.5%, polysorbate 80 of about 2.5% to 5.0%, CMC of about
1.42%, or HPMC of about 1.8% and tropicamide of about
0.004%-0.010%, more preferably about 0.005% to 0.007%, and most
preferably about 0.005%-0.006%. Micelle formation above the
critical micellar concentration may allow for micelles to spread
across the tear film surface and spread at low concentrations to
cover this surface, while at higher concentrations these micelles
becoming increasingly contracted and "squeezed" along the surface.
Not wishing to be held to particular theory, it is believed at an
optimal concentration a minimal micelle diameter is achieved before
significant multiple lamellae (layering) occurs. It is believed
that at the optimal concentration nanomicelles of about 100 to 250
nm along the surface are achieved surrounding the highly charged
and hydrophilic aceclidine, facilitating its penetration through
the very lipophilic epithelium;
Not wishing to be held to particular theory the addition of BAK
0.02% to sorbate about 0.10%, EDTA about 0.10%, in a preferred
composition of aceclidine 1.75%, mannitol 2.5%, tropicamide 0.01%,
and citrate buffer (1 to 100 mM 3-5 mM preferred) is above the BAK
critical micellar concentration. BAK, being a cationic surfactant,
and BAK micelles, creating an ionic micellar gradient with + charge
NH4+ quaternary nitrogen bring on the polar heads aggregating
outside and lipophilic alkyl chain on the hydrophobic tails
aggregating on the inside may cause significant similar aceclidine
alignment due to its dipole with quaternary NH3 nucleophilic or NH4
protonated nitrogens oriented along the outside polar heads and
more hydrophobic carbonyls C.dbd.O along hydrophobic BAK micellar
tails these preventing, greatly reducing, or moderately reducing
collisions of any nonionic aceclidine molecules--the
nucleophiles--which if oriented in solution such that randomly they
collide with another aceclidine carbonyl will result in chemical
conversion of that aceclidine via nucleophilic attack at its
targeted carbonyl, which can recur from such nucleophiles to other
aceclidines so oriented repeatedly and cause loss of stability
without such BAK orientation via 0.005% and preferably 0.01% to
0.02% most preferred micelles. The concentration of such nonionic
nucleophiles at a preferred pH in the preferred embodiment is
relatively low, but the ability of these nonionic nucleophiles to
destabilize adjacent aceclidines repeatedly without themselves
degrading is otherwise high. The result may be improved potency for
1 month plus of a mixed solution once opened in a dual chamber
bottle and mixing occurs of lyophilized aceclidine/mannitol with
the remainder of the formulation in the diluent and or improved
stability sufficient for commercialization in solution, either at
room temperature or via cold chain;
It is discovered that BAK alone does not provide sufficient
bacterial and fungal preservative efficacy but that BAK and
sorbate, or sorbate alone satisfactorily preserve diluent and or
mixed solutions of the invention;
Not to be wishing to be held to particular theory preferred
embodiments of the present invention such as containing 1.25%
hydroxypropyl methyl cellulose may have a viscosity of about 400
cps prior to instillation, yet unlike conventional high viscosity
artificial tear formulations such as Celluvisc.RTM. at about 400
cps, which may blur vision for 10-20 minutes or Liquigel.RTM. at
about 100 cps, which causes similar but slightly reduced blurring
causes only about 60 seconds of blur dissipating rapidly with an
influx of tear secretion; where both a nonnewtonian reduction in
viscosity at high shear (such as about 1/1000 sec during a blink,
and aceclidine parasympathetic trigger of tear secretion as a
sialogen may contribute.
General miotic agents, such as pilocarpine, carbachol and
phospholine diesterase, are capable of causing pupil miosis
resulting in improved near vision of presbyopic patients. However,
there is an inverse reduction in distance vision associated with
these general miotic agents from miosis at peak effect and
accommodation that is not seen with aceclidine. The
co-administration of a cycloplegic agent with aceclidine
surprisingly results in an attenuation of this reduction in
distance vision.
Comfort, safety, and efficacy of a preferred embodiment of an
ophthalmological composition of the present invention results from
the presence of a nonionic surfactant, such as cyclodextrin alpha,
beta, or gamma chains, preferably 2-hydroxypropyl beta-cyclodextrin
("HP.beta.CD"), and, sulfobutyl ether derivative of
.beta.-cyclodextrin)(Captisol.RTM.), a polyoxyl alkyl such as
polyoxyl 40 stearate and polyoxyl 35 castor oil, or a poloxamer
such as poloxamer 108 and poloxamer 407, a polysorbate such as
polysorbate 80 or Brij.RTM. 35(Brij is a registered trademark of
Uniqema Americas LLC); a viscosity enhancing agent, such as
carboxymethyl cellulose ("CMC"); a tonicity adjustor, such as
sodium chloride; a preservative, such as benzalkonium chloride and
a pH from about 5.0 to about 8.0. Further, an increase in the
concentration of the nonionic surfactant may result in reduced
redness. Specifically, increasing polysorbate from 0.10% to
0.50-1.0% results in reduced redness. Further, increasing CMC or
Carbopol.RTM. 940 from 0.50% to 1.5% w/v (preferably 1.40-1.43%
w/v) results in enhanced near vision, both quantitative improvement
and duration improvement.
The viscosity of compositions of the present invention comprising a
viscosity agent may be about 25 cps or more at 25.degree. C. and 0
shear, more preferably from about 50 to about 10,000 cps, even more
preferably from about 100 to about 5,000 cps and most preferably
from about 150 to about 450 cps. As a result of the shear force
applied to the composition as it exits the device used for
administration the viscosity may be lowered to a range from about 1
to about 25 cps at the high shear of blinking, and 50 cps to 200
cps at the low shear between blinks, allowing greater drop
retention with less spillage and less nasolacrimal drainage and
systemic absorption upon topical instillation.
Definitions
As used herein, the term "composition" is intended to encompass a
product comprising the specified ingredients in the specified
amounts, as well as any product which results, directly or
indirectly, from a combination of the specified ingredients in the
specified amounts.
The term "stabilizing", as used herein, refers to any process which
facilitates and/or enables an active agent to remain in solution.
The term "stabilizing", as used herein, also refers to any means or
process which inhibits and/or reduces the tendency of a muscarinic
agonist, including aceclidine, to degrade.
As used herein, all numerical values relating to amounts, weights,
and the like, that are defined as "about" each particular value is
plus or minus 10%. For example, the phrase "about 5% w/v" is to be
understood as "4.5% to 5.5% w/v." Therefore, amounts within 10% of
the claimed value are encompassed by the scope of the claims.
As used herein "% w/v" refers to the percent weight of the total
composition.
As used herein the term "subject" refers but is not limited to a
person or other animal.
The term muscarinic receptor agonist ("muscarinic agonist")
encompasses agonists that activate muscarinic acetylcholine
receptors ("muscarinic receptors"). Muscarinic receptors are
divided into five subtypes named M1-M5. Muscarinic agonists of the
present invention include those muscarinic agonists that
preferentially activate M1 and M3 receptors over M2, M4 and M5
receptors ("M1/M3 agonists"). M1/M3 agonists include but are not
limited to aceclidine, xanomeline, talsaclidine, sabcomeline,
cevimeline, alvameline, arecoline, milameline, SDZ-210-086, YM-796,
RS-86, CDD-0102A
(5-[3-ethyl-1,2,4-oxasdiazol-5-yl]-1,4,5,6-tetrahydropyrimidine
hydrochloride), N-arylurea-substituted 3-morpholine arecolines,
VUO255-035
(N-[3-oxo-3-[4-(4-pyridinyl)-1-piperazinyl]propyl]-2,1,3-benzothiadiazole-
-4-sulfonamide), benzylquinolone carboxylic acid (BQCA),
WAY-132983, AFB267B (NGX267), AC-42, AC-260584, chloropyrazines
including but not limited to L-687, 306, L-689-660, 77-LH-28-1,
LY593039, and any quinuclidine ring with one or more carbon
substitutions particularly that include an ester, sulfur, or 5 or 6
carbon ring structure including with substituted nitrogen(s) and or
oxygen(s), or any pharmaceutically acceptable salts, esters,
analogues, prodrugs or derivatives thereof. A preferred M1/M3
agonist is aceclidine. In a preferred embodiment, muscarinic
agonists of the present invention include those muscarinic agonist
that preferentially activate M1 and M3 over M2, M4, and M5; and
even more preferably activate M1 over M3. In a more preferred
embodiment muscarinic agonist of the present invention include
those muscarinic agonists that only activate M1.
The term "aceclidine" encompasses its salts, esters, analogues,
prodrugs and derivatives including, but not limited to, aceclidine
as a racemic mixture, aceclidine (R) enantiomer, aceclidine (S)
enantiomer, aceclidine analogues, including, but not limited to,
highly M1 selective 1,2,5 thiadiazole substituted analogues like
those disclosed in Ward. J. S. et al., 1,2,5-Thiadiazole analogues
of aceclidine as potent ml muscarinic agonists, J Med Chem, 1998,
January 29, 41(3), 379-392 and aceclidine prodrugs including but
not limited to carbamate esters.
The term "selective .alpha.-2 adrenergic receptor agonists" or
".alpha.-2 agonist" encompasses all .alpha.-2 adrenergic receptor
agonists which have a binding affinity of 900-fold or greater for
.alpha.-2 over .alpha.-1 adrenergic receptors, or 300-fold or
greater for .alpha.-2a or .alpha.-2b over a-1 adrenergic receptors.
The term also encompasses pharmaceutically acceptable salts,
esters, prodrugs, and other derivatives of selective .alpha.-2
adrenergic receptor agonists.
The term "low concentrations" or "low-dose" of alpha-2 adrenergic
receptor agonists refers to concentrations from between about
0.0001% to about 0.065% w/v; more preferably, from about 0.001% to
about 0.035% w/v; even more preferably, from about 0.01% to about
0.035% w/v; and even more preferably, from about 0.03% to about
0.035% w/v.
The term "brimonidine" encompasses, without limitation, brimonidine
salts and other derivatives, and specifically includes, but is not
limited to, brimonidine tartrate,
5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline D-tartrate, and
Alphagan.RTM..
The terms "treating" and "treatment" refer to reversing,
alleviating, inhibiting, or slowing the progress of the disease,
disorder, or condition to which such terms apply, or one or more
symptoms of such disease, disorder, or condition.
The term "pharmaceutically acceptable" describes a material that is
not biologically or otherwise undesirable (i.e. without causing an
unacceptable level of undesirable biological effects or interacting
in a deleterious manner).
As used herein, the term "pharmaceutically effective amount" refers
to an amount sufficient to affect a desired biological effect, such
as a beneficial result, including, without limitation, prevention,
diminution, amelioration or elimination of signs or symptoms of a
disease or disorder. Thus, the total amount of each active
component of the pharmaceutical composition or method is sufficient
to show a meaningful subject benefit. Thus, a "pharmaceutically
effective amount" will depend upon the context in which it is being
administered. A pharmaceutically effective amount may be
administered in one or more prophylactic or therapeutic
administrations.
The term "prodrugs" refers to compounds, including, but not limited
to, monomers and dimers of the compounds of the invention, which
have cleavable groups and become, under physiological conditions,
compounds which are pharmaceutically active in vivo.
As used herein "salts" refers to those salts which retain the
biological effectiveness and properties of the parent compounds and
which are not biologically or otherwise harmful at the dosage
administered. Salts of the compounds of the present inventions may
be prepared from inorganic or organic acids or bases.
The term "higher order aberrations" refers to aberrations in the
visual field selected from starbursts, halos (spherical
aberration), double vision, multiple images, smeared vision, coma
and trefoil.
The term "cold chain" refers to storage at temperatures from about
2 to about 8.degree. C. from manufacture to immediately prior to
administration.
The compounds of the present invention can be used in the form of
pharmaceutically acceptable salts derived from inorganic or organic
acids or bases. The phrase "pharmaceutically acceptable salt" means
those salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response and
the like and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts are well-known in the art. For
example, S. M. Berge et al. describe pharmaceutically acceptable
salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et
seq.
The salts can be prepared in situ during the final isolation and
purification of the compounds of the invention or separately by
reacting a free base function with a suitable organic acid.
Representative acid addition salts include, but are not limited to
acetate, adipate, alginate, citrate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsulfonate, digluconate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethansulfonate(isothionate), lactate,
maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,
oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate,
picrate, pivalate, propionate, succinate, tartrate, thiocyanate,
phosphate, glutamate, bicarbonate, p-toluenesulfonate and
undecanoate. Also, the basic nitrogen-containing groups can be
quaternized with such agents as lower alkyl halides such as methyl,
ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl
sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long
chain halides such as decyl, lauryl, myristyl and stearyl
chlorides, bromides and iodides; arylalkyl halides like benzyl and
phenethyl bromides and others. Water or oil-soluble or dispersible
products are thereby obtained. Examples of acids which can be
employed to form pharmaceutically acceptable acid addition salts
include such inorganic acids as hydrochloric acid, hydrobromic
acid, hyaluronic acid, malic acid, sulphuric acid and phosphoric
acid and such organic acids as oxalic acid, malic acid, maleic
acid, methanosulfonic acid, succinic acid and citric acid.
Basic addition salts can be prepared in situ during the final
isolation and purification of compounds of this invention by
reacting a carboxylic acid-containing moiety with a suitable base
such as the hydroxide, carbonate or bicarbonate of a
pharmaceutically acceptable metal cation or with ammonia or an
organic primary, secondary or tertiary amine. Pharmaceutically
acceptable salts include, but are not limited to, cations based on
alkali metals or alkaline earth metals such as lithium, sodium,
potassium, calcium, magnesium and aluminum salts and the like and
nontoxic quaternary ammonia and amine cations including ammonium,
tetramethylammonium, tetraethylammonium, methylammonium,
dimethylammonium, trimethylammonium, triethylammonium,
diethylammonium, and ethylammonium among others. Other
representative organic amines useful for the formation of base
addition salts include ethylenediamine, ethanolamine,
diethanolamine, piperidine, piperazine and the like.
The term "ester" as used herein is represented by the formula
--OC(O)A.sup.1 or --C(O)OA.sup.1, where A.sup.1 can be alkyl,
cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, a
heteroaryl group or other suitable substituent.
Compositions of the Invention
In one embodiment, the present invention is directed to an
ophthalmological composition comprising aceclidine. In a preferred
embodiment, aceclidine is at a concentration from about 0.25% to
about 2.0% w/v, more preferably from about 0.75% to about 2.5% w/v,
still more preferably from about 1.65% to about 1.85% w/v, and most
preferably about 1.75% w/v. As aceclidine is a tertiary amine with
asymmetry, both a + and - optical isomer exists (where in some
studies (+) is more potent and in others it is felt (-) may be more
potent). For the above concentrations polarimetry demonstrated an
exactly equal ratio of (+) and (-) isomer for these concentrations.
Altering this ratio could therefore alter this concentration range
proportional to a change in ratio.
The present invention is further directed to an ophthalmological
composition comprising a muscarinic agonist, preferably a nonionic
surfactant above its critical micellar concentration for the
composition, and a viscosity enhancing agent; or alternatively an
in-situ gelling agent. In preferred embodiments the initial
viscosity of the composition on topical application is above 20
cps, preferably above 50 cps, and more preferably at about 65 cps
or more at 25.degree. C. and 0 shear.
Cryoprotectants are compounds that either prevent freezing or
prevent damage to compounds during freezing. As used herein, the
term "cryoprotectant" or "cryoprotectants" include lyoprotectants.
Cryoprotectants suitable for use in the subject invention include,
but are not limited to, a polyol, a sugar, an alcohol, a lower
alkanol, a lipophilic solvent, a hydrophilic solvent, a bulking
agent, a solubilizer, a surfactant, an antioxidant, a cyclodextrin,
a maltodextrin, colloidal silicon dioxide, polyvinyl alcohol,
glycine, 2-methyl-2,4-pentanediol, cellobiose, gelatin,
polyethylene glycol (PEG), dimethyl sulfoxide (DMSO), formamide,
antifreeze protein 752 or a combination thereof.
As used herein the term "polyol" refers to compounds with multiple
hydroxyl functional groups available for organic reactions such as
monomeric polyols such as glycerin, pentaerythritol, ethylene
glycol and sucrose. Further, polyols may refer to polymeric polyols
including glycerin, pentaerythritol, ethylene glycol and sucrose
reacted with propylene oxide or ethylene oxide. In a preferred
embodiment, polyols are selected from the group consisting of
mannitol, glycerol, erythritol, lactitol, xylitol, sorbitol,
isosorbide, ethylene glycol, propylene glycol, maltitol, threitol,
arabitol and ribitol. In a more preferred embodiment, the polyol is
mannitol.
Sugars suitable for use in the present invention as cryoprotectants
include, but are not limited to, glucose, sucrose, trehalose,
lactose, maltose, fructose and dextran.
In another preferred embodiment, alcohols include, but are not
limited to, methanol.
In one embodiment, the present invention individually excludes each
cryoprotectant from the definition of cryoprotectant.
Cryoprotectants may be at present in compositions of the present
invention at a concentration from about 0.1% to about 99% w/v,
preferably from about 1% to about 50% w/v, more preferably from
about 1% to about 10% w/v.
As used herein "lower alkanols" include C1-C6 alkanols. Lower
alkanols, suitable for use in the present invention include, but
are not limited to, amyl alcohol, butanol, sec-butanol, t-butyl
alcohol, n-butyl alcohol, ethanol, isobutanol, methanol.
isopropanol and propanol.
Bulking agents suitable for use in the present invention include,
but are not limited to, saccharide, polyvinylpyrrolidone,
cyclodextrin and trehalose.
Solubilizers suitable for use in the present invention include, but
are not limited to, cyclic amide, gentisic acid and
cyclodextrins.
In a preferred embodiment, surfactants suitable for use in the
present invention include, but are not limited to, nonionic
surfactants, more preferably surfactants with a
hydrophilic-lipophilic balance ("HLB") value of 1 to 18.
In a preferred embodiment, antioxidants suitable for use in the
present invention include, but are not limited to, bisulfate,
ascorbic acid, disodium- or tetrasodium ethylenediaminetetraacetic
acid, citrate, butylated hydroxyanisole ("BHA"), butylated
hydroxytoluene ("BHT"), a sulfoxylate, propyl gallate, an amino
acid containing a thio group, and a thiol.
Nonionic surfactants suitable for the present invention include a
polysorbate, tyloxapol, a poloxamer, a cyclodextrin, vitamin E
TPGS, a polyoxyl castor oil, a polyoxyl stearate, polyethylene
glycol, a polyoxyethylene glycol alkyl ether and
2-[[10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,11,12,14,15,16,17-
-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]ethanol.
Preferred embodiments include Poloxamer 80, Poloxamer 188,
Poloxamer 407, Polysorbate 20, Polysorbate 80, ionically charged
(e.g. anionic) beta-cyclodextrins with or without a butyrated salt
(Captisol.RTM.) 2-hydroxypropyl beta cyclodextrin("HP.beta.CD"),
alpha cyclodextrins, gamma cyclodextrins, Polyoxyl 35 castor oil,
and Polyoxyl 40 hydrogenated castor oil or combinations thereof.
Further, substitution of other nonionic surfactants compatible with
ophthalmological use allows for similar formulation advantages,
which may include but is not limited to one or more of a
nonionizing surfactant such as poloxamer, poloxamer 103, poloxamer
123, and poloxamer 124, poloxamer 407, poloxamer 188, and poloxamer
338, any poloxamer analogue or derivative, polysorbate, polysorbate
20, polysorbate 40, polysorbate 60, polysorbate 80, any polysorbate
analogue or derivative, cyclodextrin,
hydroxypropyl-.beta.-cyclodextrin,
hydroxypropyl-.gamma.-cyclodextrin, randomly methylated
.beta.-cyclodextrin, .beta.-cyclodextrin sulfobutyl ether,
.gamma.-cyclodextrin sulfobutyl ether or
glucosyl-.beta.-cyclodextrin, any cyclodextrin analogue or
derivative, polyoxyethylene, polyoxypropylene glycol, an
polysorbate analogue or derivative, polyoxyethylene hydrogenated
castor oil 60, polyoxyethylene (200), polyoxypropylene glycol (70),
polyoxyethylene hydrogenated castor oil, polyoxyethylene
hydrogenated castor oil 60, polyoxyl, polyoxyl stearate, nonoxynol,
octyphenol ethoxylates, nonyl phenol ethoxylates, capryols,
lauroglycol, polyethylene glycol ("PEG"), Brij.RTM. 35, 78, 98, 700
(polyoxyethylene glycol alkyl ethers), glyceryl laurate, lauryl
glucoside, decyl glucoside, or cetyl alcohol; or zwitterion
surfactants such as palmitoyl carnitine, cocamide DEA, cocamide DEA
derivatives cocamidopropyl betaine, or trimethyl glycine betaine,
N-2(2-acetamido)-2-aminoethane sulfonic acid (ACES), N-2-acetamido
iminodiacetic acid (ADA), N,N-bis(2-hydroxyethyl)-2-aminoethane
sulfonic acid (BES),
2-[Bis-(2-hydroxyethyl)-amino]-2-hydroxymethyl-propane-1,3-diol
(Bis-Tris), 3-cyclohexylamino-l-propane sulfonic acid (CAPS),
2-cyclohexylamino-1-ethane sulfonic acid (CHES),
N,N-bis(2-hydroxyethyl)-3-amino-2-hydroxypropane sulfonic acid
(DIPSO), 4-(2-hydroxyethyl)-1-piperazine propane sulfonic acid
(EPPS), N-2-hydroxyethylpiperazine-N'-2-ethane sulfonic acid
(HEPES), 2-(N-morpholino)-ethane sulfonic acid (IVIES),
4-(N-morpholino)-butane sulfonic acid (MOBS),
2-(N-morpholino)-propane sulfonic acid (MOPS),
3-morpholino-2-hydroxypropanesulfonic acid (MOPSO),
1,4-piperazine-bis-(ethane sulfonic acid) (PIPES),
piperazine-N,N-bis(2-hydroxypropane sulfonic acid) (POPSO),
N-tris(hydroxymethyl)methyl-2-aminopropane sulfonic acid (TAPS),
N-[tris(hydroxymethyl)methyl]-3-amino-2-hydroxypropane sulfonic
acid (TAPSO), N-tris(hydroxymethyl)methyl-2-aminoethane sulfonic
acid (TES), 2-Amino-2-hydroxymethyl-propane-1,3-diol (Tris),
tyloxapol, Solulan.TM. C-24
(2-[[10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,11,12,14,15-
,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]ethanol)
and Span.RTM. 20-80 (sorbitan monolaurate, sorbitan monopalmitate,
sorbitan monostearate, and sorbitan monooleate). In certain
embodiments the addition of an anionic surfactant such as sodium
lauryl sulfate and or sodium ester lauryl sulfate may be preferred.
In other embodiments the addition of polysorbate 80 is preferred.
In addition to the above nonionic surfactants any nonionic
surfactant is suitable for use in the present invention as long as
the concentration of the nonionic surfactant is such that it is
above the critical micellar concentration for that non-ionic
surfactant. Preferably, the nonionic surfactants used in the
present invention achieve submicron diameter micelles, more
preferably less than 200 nanometers and more preferably less than
150 nanometers in diameter.
Ophthalmological in situ gels which may be substituted for or added
in addition to one or more nonionic surfactants include but are not
limited to gelatin, carbomers of various molecular weights
including carbomer 934 P and 974 P, xanthan gums, alginic acid
(alginate), guar gums, locust bean gum, chitosan, pectins and other
gelling agents well known to experts in the art.
In preferred embodiments the nonionic surfactant is polyoxyl 40
stearate at a concentration from about 1 to about 15% w/v, more
preferably at about 5.5% w/v.
In other preferred embodiments, the nonionic surfactant is
polysorbate 80 at a concentration from about 0.5% to about 10% w/v,
more preferably from about 1% to about 7% w/v and even more
preferably from about 2% to about 5% w/v, yet more preferably from
about 2.5% to about 4% w/v and most preferably at about 2.5% or
2.75% or 3% or 4% or 5% w/v.
Viscosity agents suitable for the present invention include, but
are not limited to gums such as guar gum, hydroxypropyl-guar
("hp-guar"), and xanthan gum, alginate, chitosan, gelrite,
hyaluronic acid, dextran, Carbopol.RTM. (polyacrylic acid or
carbomer) including Carbopol.RTM. 900 series including
Carbopol.RTM. 940 (carbomer 940), Carbopol.RTM. 910 (carbomer 910)
and Carbopol.RTM. 934 (carbomer 934), cellulose derivatives such as
high molecular weight carboxymethyl cellulose ("CMC"),
methylcellulose, methyl cellulose 4000, hydroxymethyl cellulose,
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyl
propyl methyl cellulose 2906, carboxypropylmethyl cellulose,
hydroxypropylethyl cellulose, and hydroxyethyl cellulose,
polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone,
gellan, carrageenan, alginic acid, carboxyvinyl polymer or
combinations thereof.
In a preferred embodiment the viscosity agent will provide a
viscosity of the total composition from about 50 to about 10,000
cps, from about 100 to about 5,000 cps or from 150 to about 450 cps
at 25.degree. C. and 0 shear.
In another preferred embodiment the viscosity agent will have an
equilibration viscosity less than 100 cps, preferably from about 15
to about 35 cps, and most preferably at about 30 cps. In a
preferred embodiment the viscosity agent is Carbopol.RTM. 940
(carbomer 940) at a concentration from about 0.05% to about 1.5%
w/v, preferably from about 0.09% to about 1.0% w/v, more preferably
at 0.09%, 0.25%, 0.5%, 0.75%, 0.9% or 1.0% w/v. In certain
combinations it has been surprisingly discovered nonionic
surfactant/viscosity combinations may result in phase separation
over time with precipitate formation. In such situations,
particularly for polyoxyls, in a preferred embodiment polyoxyl 40
stearate, and cellulose derivatives, particularly
hydroxypropylmethyl cellulose, use of a nonpolysaccharide
derivative for viscosity enhancement, such as polyacrylic acid
derivatives (carbomers, carbomer 934 or 940 in preferred
embodiments) may prevent such separation; or alternatively use of a
non polyoxyl nonionic surfactant, such as polysorbate 80 with
either a cellulose derivative or noncellulose derivative viscosity
agent may be substituted.
In another preferred embodiment, the viscosity agent is
carboxymethyl cellulose at a concentration from about 0.1% to about
2% w/v, more preferably from 0.25% to about 1.3% w/v, when at a
viscosity of 3,500 cps at 25.degree. C. in a 2% solution.
In another preferred embodiment, the viscosity agent is
hydroxypropylmethyl cellulose at a concentration from about 0.5% to
about 1.75%, and more preferably about 0.75% or 1.5%, still more
preferably from about 1.0% to about 1.5%, and most preferably at
about 1.25%.
Not wishing to be held to particularly theory, it appears the
quinuclidine nucleus of the heterocyclic nitrogen on aceclidine is
so electron rich it easily attacks surrounding compounds as well as
itself.
It is a discovery of the present invention that several
modifications may singly or in combination be used to enhance cold
chain stability storage, including in addition to in a preferred
embodiment aceclidine 1.40%-1.75%, tropicamide 0.025%-0.10% and
optionally a nonioinic surfactant such as polyoxyl 40 stearate
0.5%-10%, preferably 5.5% one or more of (See Table 3):
Acidic pH, preferably less than 5.5, preferably less than 5.0 and
most preferably at a pH of about 4.75;
Viscosity agent, preferably at 25.degree. C. viscosity of about
15-50 cps, and more preferably 20-45 cps, where a preferred
embodiment is carbomer 940 0.09%-1.5%;
Addition of a cryoprotectant, in a preferred embodiment a polyol,
preferably Mannitol 2.5%-4.0%;
Addition of a buffer, where acetate or phosphate buffers are
preferred, 2-100 mmole range with 3-5 mmole is preferred; and
Addition of a preservative, where BAK 0.015% is preferred.
The selective .alpha.-2 agonist may be included within the
composition of the present invention or applied topically
preferably just minutes before or less preferably just minutes
afterward if additional means to reduce nasal congestion or redness
is desired for sensitive subjects. Selective .alpha.-2 agonists
suitable for the present invention have minimal .alpha.-1 agonist
activity at low concentrations. For example, for brimonidine or
fadolmidine, 1% to 2% w/v is considered extremely high, 0.5% to
1.0% w/v still highly inductive of .alpha.-1 receptors and toxic
for purposes of the present invention. Further, 0.10% to 0.5% w/v
is still too high and even 0.070% to 0.10% w/v is associated with a
higher than preferred incidence of rebound hyperemia (however, for
dexmedetomidine, its greater lipophilicity and intraocular
penetration reduces rebound risk in this range). Only 0.065% w/v or
below is potentially acceptable, where for most .alpha.-2 agonists,
depending on degree of selectivity 0.050% w/v or even more
preferably 0.035% w/v or less is desired. On the other hand, some
degree of useful activity may occur at one or more orders of
magnitude further reduction of concentration. The preferred
embodiments, brimonidine, fadolmidine and guanfacine, of the
present invention preferentially stimulate .alpha.-2 adrenergic
receptors, and even more preferably .alpha.-2b adrenergic receptors
so that .alpha.-1 adrenergic receptors are not stimulated
sufficiently enough to cause excessive large vessel arteriolar
constriction and vasoconstrictive ischemia. In addition, it has
been discovered that preventing or reducing redness for drugs that
otherwise directly induce redness, such as the acetylcholine
agonist, aceclidine, enhances compliance for sensitive subjects
that may have induced redness or nasal congestion even with
formulations of the present invention that do not include an
.alpha.-2 agonist. However, because .alpha.-2 agonists are shifted
to their ionized equilibrium an acidic pH is somewhat offset by the
fact such agonists exert greater affect at neutral or alkaline pH.
Therefore, each .alpha.-2 agonist has a preferred pH range
depending on its lipophilicity and pKa value when added to the
inventive compositions with aceclidine. For the present invention
while pH range of 5.0 to 8.0 is tolerated, preferred embodiments
are at pH 5.5 to 7.5 and more preferably 6.5 to 7.0. Further, it
has been discovered that cyclodextrins and/or polyoxyl 40 stearate
as a nonionic surfactant component or as the sole nonionic
surfactant, result in a greater whitening effect when the a-2
agonist is included in the composition rather than poloxamer 407.
The .alpha.-2 agonist may optionally be applied separately or in
certain preferred embodiments with formulations of the present
invention that do not include an .alpha.-2 agonist, such as those
formulas with polyoxyl 40 stearate 5.5% w/v as the non-ionic
surfactant, although the .alpha.-2 agonist is not required except
for occasional sensitive subjects. Fadolmidine represents the
.alpha.-2 agonist with highest hydrophilicity and therefore high
surface retention for the present invention. Guanfacine is also
highly selective and hydrophilic. Brimonidine is highly selective
with moderate lipophilicity. Finally, dexmedetomidine has high
selectivity with high lipophilicity that may be used with less
efficacy for reducing redness for the purposes of the present
invention (although possibly inducing fatigue as a side effect in
some patients). In a preferred embodiment using polyoxyl 40
stearate 5.5% w/v; CMC 0.80% w/v; NaCl 0.037% w/v;
ethylenediaminetetraacetic acid ("EDTA") 0.015% w/v, borate buffer
5 mM and BAK 0.007% w/v results in redness of about 1.0 to 1.5 out
of 4 which is transient lasting about ten minutes, and by 30
minutes returns to about baseline.
In one embodiment, the selective a-2 adrenergic receptor agonist is
a compound which has binding affinity of about 900-fold or greater,
even more preferably about 1000-fold or greater, and most
preferably, about 1500-fold or greater.
The selective .alpha.-2 adrenergic receptor agonist may be present
at a concentration from between about 0.0001% to about 0.065% w/v;
more preferably, from about 0.001% to about 0.035% w/v; even more
preferably, from about 0.01% to about 0.035% w/v; and even more
preferably, from about 0.020% to about 0.035% w/v.
In one embodiment, the selective .alpha.-2 adrenergic receptor is
selected from the group consisting of brimonidine, guanfacine,
fadolmidine, dexmedetomidine,
(+)-(S)-4-[1-(2,3-dimethyl-phenyl)-ethyl]-1,3-dihydro-imidazole-2-thione,
1-[(imidazolidin-2-yl)imino]indazole, and mixtures of these
compounds. Analogues of these compounds that function as highly
selective .alpha.-2 agonists may also be used in compositions and
methods of the present invention.
In a more preferred embodiment, the selective .alpha.-2 agonist is
selected from the group consisting of fadolmidine, guanfacine and
brimonidine. In a yet more preferred embodiment the selective
.alpha.-2 agonist is brimonidine in the form of a salt at a
concentration of 0.025% to 0.065% w/v, more preferably from 0.03%
to 0.035% w/v. In a preferred embodiment, the salt is a tartrate
salt.
In another yet more preferred embodiment, the selective .alpha.-2
agonist is fadolmidine at a concentration from about 0.005% to
about 0.05% w/v, more preferably from 0.02% to about 0.035% w/v in
the form of a hydrochloride ("HCl") salt.
In another yet more preferred embodiment, the selective .alpha.-2
agonist is guanfacine at a concentration from about 0.005% to about
0.05% w/v, more preferably from 0.02% to about 0.035% w/v in the
form of an HCl salt.
In another yet more preferred embodiment, the selective .alpha.-2
agonist is dexmedetomidine at a concentration from about 0.005% to
about 0.05% w/v, more preferably from 0.04% to about 0.05% w/v in
the form of an HCl salt.
In another preferred embodiment a pH less than physiologic pH is
found to enhance the whitening effect for brimonidine, preferably
pH 4.5 to 6.5, and more preferably pH 5.5 to 6.0. However, redness
reduction is achieved at all pHs, and enhancement of aceclidine
absorption occurs at alkaline pH, such that more effect occurs from
a given concentration, and therefore while effective at pH ranges
from 4.5 to 8.0, pH range of 6.5 to 7.5 is preferred for the
present invention, and 7.0 to 7.5 most preferred.
The present invention is further directed to an ophthalmological
composition further comprising a cycloplegic agent. It is a
surprising and totally unexpected discovery of the present
invention that certain cycloplegic agents can be combined with
miotic agents, particularly for the present invention, aceclidine,
without reducing miotic onset, magnitude, or duration; and further
blunt the normally attendant spike in miotic effect coinciding with
time of peak absorption in aqueous formulations to provide a
constant miosis versus time after onset from 15 to 30 minutes to 6
to 10 hours depending on the desired formulation. The addition of
the cycloplegic agent also reduces any residual associated
discomfort that may otherwise occur soon after topical
instillation, which presumably is a result of ciliary spasms or
excessive pupillary miosis.
Cycloplegic agents suitable for the present invention include, but
are not limited to, atropine, Cyclogyl.COPYRGT. (cyclopentolate
hydrochloride), hyoscine, pirenzepine, tropicamide, atropine,
4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP), AF-DX
384, methoctramine, tripitramine, darifenacin, solifenacin
(Vesicare), tolterodine, oxybutynin, ipratropium, oxitropium,
tiotropium (Spriva), and otenzepad (a.k.a. AF-DX 116 or
11-{[2-(diethylamino)methyl]-1-piperidinyl}acetyl]-5,11-dihydro-6H-pyrido-
[2,3b] [1,4]benzodiazepine-6-one). In a preferred embodiment the
cycloplegic agent is tropicamide at a concentration from about
0.004% to about 0. 025% w/v, more preferably from about 0.005% to
about 0.015% w/v and still more preferably from about 0.005% to
about 0.011% w/v, from about 0.005% to about 0.007% w/v and from
about 0.005% to about 0.006% w/v. In another preferred embodiment
the cycloplegic agent is a mixture of tropicamide at a
concentration from about 0.04% to about 0.07% w/v or pirenzepine or
otenzepad at a concentration from about 0.002% to about 0.05%
w/v.
In a preferred embodiment, tropicamide 0.01% w/v was found to
slightly reduce brow ache, 0.030% w/v to further reduce brow ache
and from 0.04% to about 0.07% w/v to completely eliminate brow ache
without reduction of the average pupillary miosis diameter over
duration of effect. Tropicamide in preferred embodiments has
demonstrated completely unexpected sensitivity of effect, where at
about 0.04% w/v unexpectedly and very effectively reduces or
eliminates brow ache and ciliary spasm pain, becoming very
noticeably further reduced at 0.042% w/v and absent at 0.044% w/v
in a preferred embodiment with no cycloplegia (surprising due to
its common use as a pupil dilating agent). Yet, tropicamide did not
reduce the mean degree of pupil miosis, the time of onset of pupil
miosis or the subsequent visual benefits. On the contrary,
tropicamide blunted the peak miosis seen in aqueous formulations to
create a smooth consistent miotic effect over time. It allowed
modulation of peak pupil miosis to achieve a more even effect over
time with no dilation as has been found with its prior use.
Specifically, tropicamide is useful to prevent transient
constriction below 1.50 mm at 30 to 60 minutes following aceclidine
in some embodiments and to reduce transient excessive and
undesirable dimming of vision that may otherwise occur at peak
onset of about 30 minutes. As an example, an ophthalmological
composition comprising 1.53% w/v aceclidine, 5% w/v HP.beta.CD,
0.75% w/v CMC, 0.25% w/v NaCl, 0.01% w/v BAK and a phosphate buffer
at pH 7.0; or 1.45% w/v aceclidine; 5.5% w/v polyoxyl 40 stearate;
0.80% w/v CMC; 0.037% w/v NaCl; 0.015% w/v EDTA; 0.007% w/v BAK and
5 mM phosphate buffer at a pH 7.0; was varied from 0.040% w/v
tropicamide, where moderate dimming was noted, to 0.044% w/v
tropicamide where dimming became almost undetectable other than in
extremely dim light conditions. This additional pupil size
modulation with a cycloplegic agent allows aceclidine
concentrations sufficient for prolonged effect while blunting the
attendant peak excessive constriction that is undesirable as well
as any uncomfortable brow ache. Surprisingly and due to its
short-acting nature, tropicamide achieves this blunting effect
without causing mydriasis. Further, in a preferred embodiment,
tropicamide 0.014% w/v was found to reduce brow ache, 0.021% w/v to
further reduce brow ache and from 0.028% to 0.060% w/v and in some
embodiments up to 0.09% w/v to completely eliminate brow ache
without cycloplegia (i.e. paralysis of ciliary muscle of the
eye).
It has been found for a racemic 50:50 mixture of (+) and (-)
aceclidine optical isomers (where in some studies (+) is more
potent and in others it is felt (-) may be more potent) tropicamide
effects may vary depending on the ratio of aceclidine to
tropicamide. For example, in an ophthalmological composition of the
present invention comprising 1.55% w/v aceclidine, 5.5% w/v
HP.beta.CD or in a preferred embodiment polyoxyl 40 stearate, 0.75%
w/v CMC (1%=2,500 centipoise), 0.25% w/v NaCl, and 0.01% w/v BAK
and at pH 7.5, 0.042% w/v tropicamide can be differentiated from
even 0.035% w/v, with the former demonstrating normal indoor night
vision and the latter slight dimming that becomes more noticeable
at still lower concentrations. At higher concentrations, such as
from about 0.075% to about 0.090% w/v tropicamide, loss of optimal
range pupil constriction 1.50 mm to 1.80 mm range begins, and frank
mydriasis at higher concentrations begins to occur. As isomer ratio
may alter the effective concentration, this must be factored into
the clinical efficacy anticipated using aceclidine; for preferred
embodiments of the present invention a polarimeter was used to
determine an exact 50:50 isomer ratio was used (personal
communication Toronto Research Chemicals).
FIG. 1 shows the effect of a miotic agent with or without a
cycloplegic agent and with or without a carrier. Subject is an
emmetrope over the age of 45 with a baseline near vision of 20.100
and baseline distance vision of 20.20. Topical administration to
the eye of 1% w/v pilocarpine in saline solution results in an
improvement of near vision to 20.40 (8a), however this improvement
comes at the expense of a reduction in distance vision to 20.100
(8b). The addition of 0.015% w/v tropicamide results in an
improvement of near vision to 20.25 (9a) and a lessening of the
reduction of distance vision to 20.55 (9b), though in certain
instances with some induced irregular astigmatism (mildly blotched
areas in reading field of vision). Topical administration of 1.55%
w/v aceclidine in saline solution results in an improvement of near
vision to 20.40 for an extended time period of 6 hrs (10a) without
any effect on the baseline distance vision (10b). 10c and 10d show
the effects of administering aceclidine in a carrier composed of
5.5% w/v 2-hydroxypropyl beta cyclodextrin, 0.75% w/v CMC (1%=2,500
centipoise), 0.25% w/v NaCl, and 0.01% w/v BAK. As seen in 10c the
carrier increases the beneficial effect of aceclidine resulting in
better than 20.20 near vision. As seen in 10d a similar increase in
distance vision occurs. 10e and 10f show the effects of adding
0.042% w/v tropicamide to the aceclidine in the carrier. As seen in
10e near vision is improved to 20.15 with a quicker onset of
maximum visual acuity. As seen in 10f a similar improvement is seen
in distance vision. Taken together, FIG. 1 shows that aceclidine is
capable of temporarily correcting near vision in a presbyopic
subject without affecting the baseline distance vision. Similar
results can be achieved with a different miotic agent, pilocarpine,
with the addition of a cycloplegic agent such as tropicamide. A
proper drug carrier can also have a beneficial effect.
The present invention is further directed to an ophthalmological
composition further comprising a tonicity adjustor and a
preservative.
A tonicity adjustor can be, without limitation, a salt such as
sodium chloride ("NaCl"), potassium chloride, mannitol or glycerin,
or another pharmaceutically or ophthalmologically acceptable
tonicity adjustor.
Preservatives that can be used with the present invention include,
but are not limited to, benzalkonium chloride ("BAK"), sorbic acid,
oxychloro complex, citric acid, chlorobutanol, thimerosal,
phenylmercuric acetate, disodium ethylenediaminetetraacetic acid,
phenylmercuric nitrate, perborate or benzyl alcohol. In a preferred
embodiment the preservative is BAK, sorbic acid, oxychloro complex
or a combination thereof. In a yet more preferred embodiment BAK is
at a concentration of about 0.001% to about 1.0% w/v, more
preferably at a concentration of about 0.007%, 0.01% or 0.02% w/v.
In another preferred embodiment the preservative is perborate at a
concentration of 0.01% to about 1.0% w/v, more preferably at a
concentration of about 0.02% w/v.
Various buffers and means for adjusting pH can be used to prepare
ophthalmological compositions of the invention. Such buffers
include, but are not limited to, acetate buffers, citrate buffers,
phosphate buffers and borate buffers. It is understood that acids
or bases can be used to adjust the pH of the composition as needed,
preferably of 1 to 10 mM concentration, and more preferably about 3
mM or 5 mM. In a preferred embodiment the pH is from about 4.0 to
about 8.0, in a more preferred embodiment the pH is from about 5.0
to about 7.0.
The present invention is further directed to an ophthalmological
composition further comprising an antioxidant. Antioxidants that
can be used with the present invention include but are not limited
to disodium ethylenediaminetetraacetic acid at a concentration from
about 0.005% to about 0.50% w/v, citrate at a concentration from
about 0.01% to about 0.3% w/w, dicalcium diethylenetriamine
pentaacetic acid ("Ca2DTPA") at a concentration from about 0.001%
to about 0.2% w/v, preferably about 0.01% w/v Ca2DTPA which can be
formulated by adding 0.0084% w/v Ca(OH).sub.2 and 0.0032% w/v
pentetic acid to the formulation and mixing slowly. Further
combinations of antioxidants can be used. Other antioxidants that
can be used with the present invention include those well known to
experts in the art such as ethylenediaminetetraacetic acid at a
concentration from about 0.0001% to about 0.015% w/v.
It is a surprising and unexpected discovery that topical
formulations of the present invention, particularly one of the
preferred embodiments comprising aceclidine 1.35% to 1.55% w/v;
5.5% w/v polyoxyl 40 stearate; 0.80% w/v CMC; 0.037% w/v NaCl;
0.015% w/v EDTA; 0.007% w/v BAK; and 5 mM phosphate buffer at pH
7.0 result in considerably prolonged contact lens wear and comfort
after a single topical instillation daily. The single daily use of
the preferred embodiments allowed a subject with dry eye to sleep
in his lenses for one-week periods where previously even after a
single night vision would be blurred and contact lenses coated with
film requiring removal and cleaning or replacement (see Example
7).
In preferred embodiments, an ophthalmological composition of the
present invention comprises aceclidine, a cryoprotectant,
optionally a cycloplegic agent, a nonionic surfactant at a
concentration from about 1% to about 5% w/v and a viscosity agent
at a concentration of about 0.75% to about 1.6% w/v, preferably
about 1.25% to about 1.5% w/v.
The following representative embodiments are provided solely for
illustrative purposes and are not meant to limit the invention in
any way.
Representative Embodiments
In one embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75% w/v; and mannitol at a
concentration of about 2.5% w/v.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75% w/v; mannitol at a
concentration of about 2.5% w/v; and tropicamide at a concentration
of about 0.02% w/v.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75% w/v; mannitol at a
concentration of about 2.5% w/v; polysorbate 80 at a concentration
of about 5.0% w/v; carboxymethyl cellulose at a concentration of
about 1.4% w/v; BAK at a concentration of about 0.015% w/v; and
phosphate buffer at a concentration of about 3 mM, wherein the pH
is about 5.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75% w/v; mannitol at a
concentration of about 2.5% w/v; polysorbate 80 at a concentration
of about 0.5% w/v; NaCl at a concentration from about 0.10% to
about 0.50% w/v; Carbopol.RTM. 940 at a concentration of about
0.95% w/v; BAK at a concentration of about 0.01% w/v; and phosphate
buffer at a concentration of about 3 mM, wherein the pH is about
5.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75% w/v; mannitol at a
concentration of about 2.5% w/v; polysorbate 80 at a concentration
of about 2.0% w/v; NaCl at a concentration of about 0.50% w/v
Carbopol.RTM. 940 at a concentration of about 1.5% w/v; BAK at a
concentration of about 0.015% w/v; and phosphate buffer at a
concentration of about 3 mM, wherein the pH is about 5.25.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75% w/v; mannitol at a
concentration of about 2.5% w/v; polysorbate 80 at a concentration
of about 0.25% w/v; NaCl at a concentration of about 0.1% w/v;
boric acid at a concentration of about 0.12% w/v; Carbopol.RTM. 940
at a concentration of about 0.95% w/v; and BAK at a concentration
of about 0.015% w/v; wherein the pH is about 5.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75% w/v; mannitol at a
concentration of about 2.5% w/v; polysorbate 80 at a concentration
of about 0.50% w/v; NaCl at a concentration of about 0.05% w/v;
boric acid at a concentration of about 0.2% w/v; Carbopol.RTM. 940
at a concentration of about 0.95% w/v; BAK at a concentration of
about 0.01% w/v; and phosphate buffer at a concentration of about 3
mM, wherein the pH is about 5.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75% w/v; mannitol at a
concentration of about 2.5% w/v; polysorbate 80 at a concentration
of about 0.1% w/v; boric acid at a concentration of about 0.2% w/v;
Carbopol.RTM. 940 at a concentration of about 0.9% w/v; BAK at a
concentration of about 0.05% w/v; and phosphate buffer at a
concentration of about 3 mM, wherein the pH is about 5.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75% w/v; mannitol at a
concentration of about 2.5% w/v; polysorbate 80 at a concentration
of about 0.1% w/v; NaCl at a concentration of about 0.1% w/v; boric
acid at a concentration of about 0.12% w/v; Carbopol.RTM. 940 at a
concentration of about 0.95% w/v; BAK at a concentration of about
0.01% w/v; and phosphate buffer at a concentration of about 3 mM,
wherein the pH is about 5.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75% w/v; tropicamide at a
concentration of about 0.01% w/v; mannitol at a concentration of
about 2.5% w/v; polysorbate 80 at a concentration of about 5.0%
w/v; CMC at a concentration of about 1.4% w/v; BAK at a
concentration of about 0.015% w/v; and phosphate buffer at a
concentration of about 3 mM, wherein the pH is about 5.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75% w/v; tropicamide at a
concentration of about 0.02% w/v; mannitol at a concentration of
about 2.5% w/v; polysorbate 80 at a concentration of about 0.25%
w/v; NaCl at a concentration of about 0.1% w/v; boric acid at a
concentration of about 0.12% w/v; Carbopol.RTM. 940 at a
concentration of about 0.95% w/v; and BAK at a concentration of
about 0.01% w/v. wherein the pH is about 5.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75% w/v; tropicamide at a
concentration of about 0.015% w/v; mannitol at a concentration of
about 2.5% w/v; polysorbate 80 at a concentration of about 0.75%
w/v; NaCl at a concentration of about 0.05% w/v; boric acid at a
concentration of about 0.2% w/v; Carbopol.RTM. 940 at a
concentration of about 0.95% w/v; BAK at a concentration of about
0.01% w/v; and phosphate buffer at a concentration of about 3 mM.
wherein the pH is about 5.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75% w/v; tropicamide at a
concentration of about 0.025% w/v; mannitol at a concentration of
about 2.5% w/v; polysorbate 80 at a concentration of about 0.1%
w/v; boric acid at a concentration of about 0.2% w/v; Carbopol.RTM.
940 at a concentration of about 0.9% w/v; BAK at a concentration of
about 0.05% w/v; and phosphate buffer at a concentration of about 3
mM. wherein the pH is about 5.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75% w/v; tropicamide at a
concentration of about 0.02% w/v; mannitol at a concentration of
about 2.5% w/v; polysorbate 80 at a concentration of about 0.1%
w/v; NaCl at a concentration of about 0.1% w/v; boric acid at a
concentration of about 0.12% w/v; Carbopol.RTM. 940 at a
concentration of about 0.95% w/v; BAK at a concentration of about
0.01% w/v; and phosphate buffer at a concentration of about 3 mM.
wherein the pH is about 5.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.75% w/v; tropicamide at a
concentration of about 0.040% w/v; polyoxyl 40 stearate at a
concentration of about 5.0% w/v; mannitol at a concentration of
about 2.5% w/v; acetate or phosphate buffer at a concentration of
about 3.0 mM; and BAK at a concentration of about 0.01% w/v,
wherein said composition has a pH of about 4.75.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.55% w/v; tropicamide at a
concentration of about 0.040% w/v; polyoxyl 40 stearate at a
concentration of about 5.0% w/v; citric acid monohydrate at a
concentration of about 0.1% w/v; mannitol at a concentration of
about 4.0% w/v; Carbopol.RTM. 940 at a concentration of 0.09% w/v;
and acetate or phosphate buffer at a concentration of about 3.0 mM;
wherein said composition has a pH of about 5.0.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.50% w/v; tropicamide at a
concentration of about 0.042% w/v; polyoxyl 40 stearate at a
concentration of about 5.5% w/v; mannitol at a concentration of
about 2.5% w/v; phosphate buffer at a concentration of about 3.0
mM; Carbopol.RTM. 940 at a concentration of about 0.85% w/v; and
BAK at a concentration of about 0.01% w/v, wherein said composition
has a pH of about 4.75.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.45% w/v; tropicamide at a
concentration of about 0.042% w/v; polyoxyl 40 stearate at a
concentration of about 5.5% w/v; citric acid monohydrate at a
concentration of about 0.1% w/v; acetate buffer at a concentration
of about 3.0 mM; and Carbopol.RTM. 940 at a concentration of about
0.75% w/v, wherein said composition has a pH of about 4.75.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of about 1.45% w/v; tropicamide at a
concentration of about 0.042% w/v; polyoxyl 40 stearate at a
concentration of about 5.5% w/v; mannitol at a concentration of
about 2.0% w/v; citric acid monohydrate at a concentration of about
0.1% w/v; phosphate buffer at a concentration of about 3.0 mM; and
Carbopol.RTM. 940 at a concentration of about 1.0% w/v, wherein
said composition has a pH of about 4.75.
In another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine; about 2.5% w/v mannitol; about 2.75%
w/v polysorbate 80; and about 1.25%; 1.0%-1.80% w/v
hydroxypropylmethyl cellulose (depending on its molecular
weight).
In another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine; about 0.005% to about 0.011%
tropicamide; about 2.5% w/v mannitol; about 2.75% w/v polysorbate
80; and about 1.25%; 1.0%-1.80% w/v hydroxypropylmethyl cellulose
(depending on its molecular weight).
In another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine; about 0.010% w/v tropicamide; about
2.5% w/v mannitol; about 5.0% w/v polysorbate 80; about 1.40% w/v
carboxymethyl cellulose high viscosity; about 3 mM phosphate
buffer; and about 0.010% BAK=as preservative, with a pH of about
5.0.
In another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine; about 0.006% w/v tropicamide; about
2.5% w/v mannitol; about 2.5% w/v polysorbate 80; about 1.25%;
1.0%-1.80% w/v hydroxypropylmethyl cellulose (depending on its
molecular weight); about 3 mM phosphate buffer; and about 0.020%
BAK=as preservative, with a pH of about 5.0.
In another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine; about 0.006% w/v tropicamide; about
2.5% w/v mannitol; about 2.5% w/v polysorbate 80; about 1.25%;
1.0%-1.80% w/v hydroxypropylmethyl cellulose (depending on its
molecular weight); about 3 mM phosphate buffer; about 0.50% w/v
NaCl; and about 0.020% BAK=as preservative, with a pH of about
5.0.
In another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine; about 2.5% w/v mannitol; about 3.5% w/v
polysorbate 80; about 1.25%; 1.0%-1.80% w/v hydroxypropylmethyl
cellulose (depending on its molecular weight); about 3 mM phosphate
buffer; about 0.50% w/v NaCl; and about 0.020% BAK or 0.15% sorbic
acid as preservative, with a pH of about 5.0.
In another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine; about 2.5% w/v mannitol; about 3.5% w/v
polysorbate 80; and about 1.25%; 1.0%-1.80% w/v hydroxypropylmethyl
cellulose (depending on its molecular weight);
In another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine; about 2.5% w/v mannitol; about 3.5% w/v
polysorbate 80; about 1.25%; 1.0%-1.80% w/v hydroxypropylmethyl
cellulose (depending on its molecular weight); and one or more
excipient selected from the group consisting of about 0.50% w/v
sodium chloride, about 0.02% w/v benzalkonium chloride, about 0.10%
w/v sorbate, about 0.01% w/v ethylenediaminetetraacetic acid (EDTA)
and 0.10% w/v citric acid.
In another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine; about 2.5% w/v mannitol; about 0.01%
w/v tropicamide; about 0.1% w/v sodium citrate, anhydrous; about
0.02% w/v benzalkonium chloride; about 0.12% w/v sorbic acid; about
0.1% w/v disodium edetate dihydrate; about 4.0% w/v polysorbate 80;
and about 1.25% w/v hydroxypropylmethyl cellulose, wherein the pH
is about 5.0.
In another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine; about 2.5% w/v mannitol; about 0.01%
w/v tropicamide; about 0.1% w/v sodium citrate, anhydrous; about
0.02% w/v benzalkonium chloride; about 0.1% w/v sorbic acid; about
0.1% w/v EDTA; about 3.5% w/v polysorbate 80; and about 1.25%;
1.0%-2.25% w/v hydroxypropylmethyl cellulose (depending on its
molecular weight), wherein the pH is about 5.0.
In another embodiment, the ophthalmological composition comprises:
about 1.75% w/v aceclidine; about 2.5% w/v mannitol; about 0.01%
w/v tropicamide; about 3 mM phosphate buffer; about 0.02% w/v
benzalkonium chloride; about 0.1% w/v sorbic acid; about 0.1% w/v
citrate; about 3.5% w/v polysorbate 80; and about 1.25%;
0.25%-2.25% w/v hydroxypropylmethyl cellulose (depending on its
molecular weight); wherein the pH is about 5.0.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of 1.5% w/v, mannitol at a
concentration of 2.5% w/v.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of 1.55% w/v, mannitol at a
concentration of 2.5% w/v.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of 1.6% w/v, mannitol at a
concentration of 2.5% w/v.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of 1.65% w/v, mannitol at a
concentration of 2.5% w/v.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of 1.7% w/v, mannitol at a
concentration of 2.5% w/v.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of 1.75% w/v, mannitol at a
concentration of 2.5% w/v.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of 1.80% w/v, mannitol at a
concentration of 2.75% w/v and Carbopol.RTM. 940 at a concentration
of 0.09% w/v.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of 1.48% w/v, mannitol at a
concentration of 1.5% w/v and Carbopol.RTM. 940 at a concentration
of 0.50% w/v.
In another embodiment, the ophthalmological composition comprises:
aceclidine at a concentration of 1.80% w/v, mannitol at a
concentration of 2.5% w/v and Carbopol.RTM. 940 at a concentration
of 0.9% w/v.
In another embodiment the ophthalmological compositions are those
in Tables 1 and 2.
TABLE-US-00001 TABLE 1 Representative Aceclidine Compositions
Formula A B C D E F G H I Aceclidine 1.75% 1.35% 1.40% 2.40% 1.50%
1.00% 0.75% 0.55% 1.50% Polysorbate 80 -- 1.00% -- 2.00% 1.00%
0.25% 4.00% 4.00% -- Poloxamer 407 -- -- -- -- 0.10% 1.00% -- -- --
Poloxamer 188 -- -- -- 2.00% 0.10% 0.25% -- -- 1.00% Cyclodextrin
-- -- 1.00% -- 0.50% 0.25% -- 1.00% 1.00% CMC -- -- 0.75% 0.85%
1.00% 0.80% 1.10% 1.20% 0.25% (2% = 3500 cps) NaCl 0.90% 0.80%
0.90% 0.75% 0.75% 0.85% 0.90% 0.90% 0.90% K Sorbate 0.10% 0.10%
0.10% 0.12% 0.12% 0.10% 0.10% 0.10% 0.10%
TABLE-US-00002 TABLE 2 Representative Aceclidine Compositions
Formula J K L Aceclidine 1.75% 1.75% 1.75% Tropicamide 0.010%
0.010% 0.006% Mannitol -- 2.00% 2.50% Polysorbate 80 1.00% 2.00%
4.00% Poloxamer 407 0.50% 0.20% -- Poloxamer 188 -- 0.20% --
Cyclodextrin -- 0.20% -- CMC (2% = 3500 cps) 1.00% 0.85% 1.30% NaCl
0.90% 0.65% 0.90% K Sorbate 0.10% 0.10% 0.10%
The following Examples are provided solely for illustrative
purposes and are not meant to limit the invention in any way.
EXAMPLES
Example 1 Effect of Aceclidine on Vision of Subjects Aged 47 to 67
Years
Table 3 demonstrates the effect on the near focus ability of
presbyopic subjects before and after ophthalmological
administration of a composition containing aceclidine. Each
composition included aceclidine in the concentrations indicated and
5.5% w/v HP.beta.CD, 0.75% w/v CMC, 0.25% w/v NaCl and 0.01% w/v
BAK. Additionally, compositions administered to subjects 4 and 5
included 0.125% w/v tropicamide. As aceclidine is an enantiomer,
the clinical effectiveness may vary with different ratios. For the
present studies a nearly exact 50:50 ratio of stereoisomers was
measured as best determined by polarimetry.
TABLE-US-00003 TABLE 3 Effects of aceclidine on vision of
presbyopic patients. Vision Baseline Post Gtt 15'' Aceclidine R Pre
R Post Date # Age % Dist L Pre Dist R Pre Near L Pre Near Dist L
Post Dist R Post Near L Post Near Effect (h) Aug. 21, 1 67 1.5
20.20 20.30 20.60 20.60 20.20 20.20 20.15 20.15 9.00 2013 Aug. 22,
2 52 1.5 20.30 20.30 20.50 20.50 20.25 20.25 20.25 20.20 8.00 2013
Aug. 23, 3 61 1.5 20.40 20.30 20.60 20.50 20.20 20.25 20.15 20.15
8.00 2013 Aug. 23, 4 61 1.1 20.20 20.25 20.80 20.50 20.15 20.15
20.20 20.15 12.00 2013 Aug. 23, 5 53 1.1 20.20 20.20 20.60 20.60
20.20 20.20 20.25 20.25 7.00 2013 Aug. 24, 6 47 1.5 20.25 20.25
20.100 20.100 20.20 20.20 20.15 20.15 8.00 2013 Aug. 25, 7 58 1.5
20.30 20.200 20.100 20.30 20.25 20.30 20.20 20.30 8.00 2013
As seen in Table 3 all subjects had less than perfect near vision
(20.20) in both the left and right eye (object at 15 inches from
the eye) and most subjects had less than perfect distance vision
before administration of the composition. After administration of
the composition all subjects experienced an improvement in their
near vision that lasted from 7 to 12 hours. Surprisingly, the
majority of subjects also experienced improvement of their distance
vision for the same time period. Still more surprisingly the
improvement in near point was much closer than 16'' typically
required for comfortable reading, in some cases to about 8.5'' more
commonly seen in individuals 30 or less. The addition of
tropicamide, a cycloplegic agent, had no additive or deleterious
effect on vision correction.
Example 2 Effect of Concentration of Concentration of Aceclidine
and Tropicamide
TABLE-US-00004 TABLE 4 Effect of concentration of concentration of
aceclidine and tropicamide. #1 #2 #3 #4 #5 (OD) #5 (OS) #6 #7
Brimonidine 0.03% 0.03% 0.03% 0.03% 0.03% 0.03% 0.03% Poloxamer 407
5.5% HPBCD 5.5% 5.5% 5.5% 5.5% 5.5% 5.5% 5.5% Aceclidine 1.5% 1.5%
0.75% 1.1% 1.1% 1.1% 1.1% 1.1% Tropicamide 0.014% 0.021% 0.028%
0.042% 0.062% NaCl 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% 0.25%
CMC 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% BAK 0.1% 0.1%
0.1% 0.1% 0.1% 0.1% 0.1% 0.1% Redness (15 m) 3+ 1 0.5 0.5 0 0 0 0
Redness (30 m) 1.5 0.5 0.25 0.25 0 0 0 0 Brow Ache (60 m) 2+ 2+ 2
0.5 0.5 0.0 0.0 0.0 Stinging (10 m) 2 2 0.5 0 0 0 0 0 BD-OD 20.20
20.20 20.20 20.20 20.20 20.20 20.20 20.20 BD-OS 20.25 20.25 20.25
20.25 20.25 20.25 20.25 20.25 BN-OD 8 pt 8 pt 8 pt 8 pt 8 pt 8 pt 8
pt 8 pt BN-OS 7 pt 7 pt 7 pt 7 pt 7 pt 7 pt 7 pt 7 pt BP-photopic 3
mm 3 mm 3 mm 3 mm 3 mm 3 mm 3 mm 3 mm BP-mesopic 5 mm 5 mm 5 mm 5
mm 5 mm 5 mm 5 mm 5 mm Miosis start (m) 15 15 15 15 15 15 15 15
Miosis (OU) (1 hr) 1.63 mm 1.63 mm 2.0-2.5 mm 1.63 mm 1.63 mm 1.63
mm 1.63 mm 1.70 mm Distance (OU) (20 m) 20.20 20.20 20.20 20.20
20.20 20.20 20.20 20.20 Distance (OD) (1 hr) 20.15 + 2 20.15 + 2
20.20 20.15 + 2 20.15 + 2 20.15 + 2 20.15 + 2 20.15 + 2 Distance
(OS) (1 hr) 20.15 + 2 20.15 + 2 20.20 20.15 + 2 20.15 + 2 20.15 + 2
20.15 + 2 20.15 + 2 Disance (OU) (1 hr) 20.10 - 3 20.10 - 3 20.15
20.10 - 3 20.10 - 3 20.10 - 3 20.10 - 3 20.10 - 3 Near (OU) (20 m)
4 pt 4 pt 4 pt 4 pt 4 pt 4 pt 4 pt 4 pt Time (hr) 12.5 12.5 6.5 11
10 10 Abbreviations: (C) indicates corrected vision, (m) indicates
minutes, (hr) indicates hour, mm indicates millimeters, BD
indicates baseline distance vision; BN indicates baseline near
vision, BP indicates baseline pupil size, OD indicates right eye;
OS indicates left eye and OU indicates both eyes.
Abbreviations: (C) indicates corrected vision, (m) indicates
minutes, (hr) indicates hour, mm indicates millimeters, BD
indicates baseline distance vision; BN indicates baseline near
vision, BP indicates baseline pupil size, OD indicates right eye;
OS indicates left eye and OU indicates both eyes.
All percentages are w/v. "pt" reflects size of print materials, 4
being equivalent to 20/20 vision and 3 to 20/15 vision.
"Time" refers to duration of the effect.
As seen in Table 4 aceclidine at a concentration of at least 1.1%
w/v was able to reduce the size of the pupil to 1.63 mm 1 hour
after topical instillation resulting in corrected near and distance
vision for at least 10 hours. Lowering of the concentration of
aceclidine to 0.75% w/v (formula #3) reduced the miotic effect to
2.0-2.5 mm after 1 hour and vision correction lasted only 6.5
hours. The addition of 0.03% w/v brimonidine reduced redness of the
eye (4 out of 4 without brimonidine, not shown) to 1.5 out of 4
within 30 minutes after topical instillation which was maintained
for the entire time vision was corrected. Switching the nonionic
surfactant to HP.beta.CD (formulas #2-6) further reduced the
redness of the eye. Lowering of the concentration of aceclidine to
0.75% w/v (formula #3) further reduced eye redness but as mention
above also reduced the vision correction duration of the
formula.
A brow ache and stinging in the eye were noticeable in formulas
#1-3 with a 2 out of 4 level of pain which was also associated with
feelings of slight nausea, upset stomach and fatigue. Surprisingly,
the addition of a cycloplegic agent, tropicamide, reduced brow ache
and stinging to 0.5 out of 4 and 0 out of 4 respectively with brow
ache dissipating after 60 minutes (formula #4). Further, the
raising of the concentration of aceclidine to 1.1% w/v restored the
longer duration of corrected vision seen in formulas #1-2 without
increasing eye redness. However, upon re-topical instillation of
formula #4 at the end of the 10 hours noticeable brow ache
occurred. Topical instillation of formula #5 (OD) and (OS), with
increased tropicamide concentrations, following formula #4 relieved
the brow ache experienced with re-installation of formula #4. Upon
a 3.sup.rd topical instillation, at the end of the effective
duration of formula #5, re-topical instillation of formula #5 again
led to considerable brow ache. Once again, in formula #6, raising
the concentration of tropicamide was able to overcome the brow
ache. Additionally, and unexpectedly, tropicamide, despite being a
cycloplegic agent, had no effect on pupil miosis or vision
correction. Surprisingly, the addition of tropicamide resulted in a
prolonged duration of optimal pupil size constriction.
To determine the effect of brimonidine on pupil miosis, formula #7,
was administered. Administration of formula #7 resulted in only a
slight decrease in pupil miosis to 1.70 mm with identical distance
and near vision improvement to that of formula #5. A 2-3+
conjunctival injection was noted.
All baseline vision data was based on vision corrected with
distance contact lenses. Near vision was noted by subject as
outstanding from 8 inches to the horizon at 1.5 hours after
installation. A Marco Autorefractor with infrared camera and
superimposed pupil calibration scale was used for all pupil size
measurements. Once an image was selected it remained on screen
allowing accurate calibration.
Example 3 Effect of Concentration of Aceclidine, Brimonidine,
Guanfacine, Fadolmidine, Tropicamide and Additives
TABLE-US-00005 TABLE 5 Effect of concentration of aceclidine,
brimonidine, guanfacine, fadolmidine, tropicamide and additives.
AB2T AB4T AB6T AB11T AB12T PROPH13 Aceclidine 1.55 1.55 1.55 1.55
1.85 1.55 Brimonidine 0.037 0.037 0.037 0.037 Fadolmidine 0.037
Guanfacine 0.037 HPBCD 5.5 5.5 5.5 5.5 5.5 5 Tropicamide 0.043
0.043 0.043 0.043 0.042 0.043 CMC* 0.075 0.075 0.075 0.075 0.075
0.075 NaCl 0.025 0.025 0.025 0.025 0.025 0.025 BAK 0.01 0.01 0.01
0.01 0.01 0.01 Glycerin 0.1 0.1 0.1 Poloxamer 0.1 0.05 188 Polyoxyl
0.05 40 stearate pH 6.5 7.5 7.5 7.5 7.0 7.5 nasal 0 0 0 0 0 0
congestion stinging 0.75 0 1.5 3.5 0 1.5 initial stinging, 0.5 0 0
wash 0 0 3 min out redness 0 0 1 D/C 1 1 initial redness 0 0 0 D/C
0 0 15 min whitening 0 0 0 D/C 1.5 1.5 pain 0 0 0 D/C 0 0 vision
near 20.30 20.15 20.15 D/C 20.15 20.15 vision 20.20 20.20 20.20 D/C
20.20 20.20 distance onset (min) 20 12 16 D/C 12 16 duration 5.5
7.5 7.5 D/C 7.5 7.5 (hrs) color clear yellow yellow yellow yellow
yellow OVERALL 2.5 3.9 3.8 0 4 3.9 *1% = 2,500 cps
All percentages are w/v. Scores for nasal congestion, stinging
initial, stinging, 3 min, redness initial, redness 15 min,
whitening, pain and overall are out of 4.
"pt" reflects size of print materials, 4 being equivalent to 20/20
vision and 3 to 20/15 vision.
Baseline vision was 20.20 both eyes for distance; 20.70 right eye
unaided for near; 20.80 left eye for near (best @ 16'').
D/C stands for discontinued after eye washing due to intolerable
stinging.
Aceclidine at a concentration of 1.55% w/v was able to reduce the
size of the pupil to about 1.63 mm 30 minutes after topical
instillation resulting in corrected near and distance vision to
20.20 or better for at least 6 hours, with noticeable affect
lasting about 7.5 hours as seen in Table 5. Lowering of the
concentration of aceclidine to 1.25% w/v (not shown) resulted in
useful near vision improvement to about 20.25-20.30, but not as
effective as at the higher dose range alkaline pH resulted in
quicker onset, longer duration, and greater effect. The addition of
0.037% w/v brimonidine reduced redness of the eye (4 out of 4
without brimonidine, not shown) to baseline within 15 minutes after
topical instillation which was maintained for the about the entire
time vision was corrected. Adding glycerin 0.10% w/v noticeably
reduced stinging. Adding instead poloxamer 188 0.05% w/v and
polyoxyl 40 stearate 0.05% w/v however reduced initial stinging
further but was more viscous. The combination of glycerin 0.1% w/v,
poloxamer 188 0.1% w/v at a pH of 6.5 was noticeably reduced in
onset, duration, comfort and effectiveness. AB11T did not include
glycerin, poloxamer 188, or polyoxyl 40 stearate, which resulted in
substantial stinging and discontinuation of the experiment with eye
flush irrigation immediately after topical instillation.
Substitution of guanfacine 0.037% w/v in AB12T for brimonidine
resulted in minimal initial redness with prolonged redness
reduction and some degree of whitening, and appeared to provide
overall the best cosmesis though requiring slightly higher
aceclidine concentration for optimal effect.
All baseline vision data was based on vision corrected with
distance contact lenses. Near vision was noted by subject as
outstanding from 8 to 10 inches to the horizon at 30 minutes after
installation for AB4T and AB6T.
AB4T and AB6T were repeated both monocularly and binocularly.
Substantial improvement in depth perception, near point acuity to 3
pt (20.15), and near point distance (8'', 20.20) was noted when
both eyes were treated vs. monocular treatment. Monocular treatment
resulted in worsening of vision with both eyes open versus testing
only the treated eye.
Example 4 Effect of Concentration of Aceclidine, Brimonidine,
Tropicamide, and Additives
TABLE-US-00006 TABLE 6 Effect of concentration of aceclidine,
brimonidine, tropicamide, and additives. #8 #9 #10 #11 #12 #13 #14
Aceclidine 1.61% 1.61% 1.61% 1.61% 1.61% 1.53% 1.53% Tropicamide
0.042% 0.042% 0.042% 0.042% 0.042% 0.044% 0.044% Brimonidine 0.042%
0.042% 0.042% 0.042% 0.042% CMC 0.75% 0.75% 0.80% 0.87% 0.75% 0.75%
0.75% NaCl 0.25% 0.25% 0.50% 0.50% 0.25% 0.50% 0.50% BAK 0.01%
0.01% 0.01% 0.01% 0.01% 0.01% 0.01% pH 7.00 7.00 7.00 7.00 8.00
7.00 7.00 phosphate buffer 5 mM 5 mM 5 mM 6 mM 5 mM 5 mM borate
buffer 5 mM Onset (min) 15 15 15 15 15 15 15 Duration (hrs) 7 7
10-12 10-12 7 9 7 Pupil range (mm) 1.5-1.7 1.5-1.7 1.5-1.7 1.5-1.7
1.5-1.7 1.8-2.0 1.8-2.0 Dimming 0-4 1.5 1.5 1.5 1.5 1.5 0.5 0.5
Sting 0-4 1 1 1 1 1 1 1 Ache 0-4 0.25 0.25 0.25 0.25 0.25 0.00 0.00
Redness 0-4 0.5 0.5 0.5 0.5 1.5 1.0 0.5 Other watery watery sl
thicker sl residue watery watery watery Overall 0-5 3.5 3.5 4 4 2.5
4.5 4.75 #15 #16 #17 #18 #19 #20 #21 Aceclidine 1.53% 1.53% 1.53%
1.53% 1.45% 1.65% 1.75% Tropicamide 0.044% 0.044% 0.044% 0.044%
0.042% 0.044% 0.035% Brimonidine 0.042% 0.042% 0.042% 0.042% 0.042%
0.042% CMC 0.80% 0.80% 0.80% 0.80% 0.75% 0.75% 0.75% NaCl 0.50%
0.75% 0.75% 1.00% 0.25% 0.25% 0.25% BAK 0.01% 0.01% 0.01% 0.01%
0.01% 0.01% 0.01% pH 7.00 7.00 8.00 7.00 7.00 7.00 8.00 phosphate
buffer 5 mM 5 mM 5 mM 5 mM 5 mM 5 mM 6 mM borate buffer Onset (min)
15 15 15 15 15 15 15 Duration (hrs) 10-12 9 9 7 7 7 7 Pupil range
(mm) 1.8-2.0 1.8-2.0 1.8-2.0 1.8-2.0 1.8-2.1 1.8-2.1 1.8-2.2
Dimming 0-4 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Sting 0-4 1 1 1 1 1 1 1
Ache 0-4 0.00 0.00 0.00 0.00 0.00 0.25 0.00 Redness 0-4 0.5 0.5 1.0
0.5 0.5 0.5 0.5 Other sl thicker sl thicker sl thicker thicker
watery watery watery Overall 0-5 5 5 5 4 4 4 4
As seen in Table 6, formulas #8-9, an increase in brimonidine to
0.42% w/v resulted in redness reduction to 0.5, while 0.75% w/v CMC
resulted in a watery consistency. Unexpectedly, increasing CMC from
0.75% w/v to a range of 0.80% w/v to 0.87% w/v and increasing NaCl
from 0.25% w/v to 0.75% w/v in formulas #10-11 resulted in a
thicker consistency and an increased residence time from 7 hours to
10-12 hours and decreased the amount of drug that drained into the
nasolacrimal duct. This decreased drug delivery to the nasal
passages results in less nasal congestion.
In formulas #13-18 a decrease in the amount of aceclidine from
1.61% to 1.53% w/v resulted in a pupil size range from 1.8-2.0 mm.
Dimming as a result of the restriction of the pupil decreased
linearly from 1.5 to 0.5 with the decreased amount of aceclidine.
Specifically, the 1.8 to 2.0 mm pupil created 41% more light than
the 1.5 to 1.7 mm pupil. Surprisingly, the 1.8 to 2.0 mm pupil had
a near depth increase of 1.75 D. This is only a 0.25 D loss from
the beneficial 2.00 D seen with the 1.5-1.7 mm range. Thus, the
1.80 to 2.0 mm range produces 41% more light while still allowing
the full benefit of increased near vision in individuals under 60
years of age; whereas, individuals 60 years of age and over still
experience total computer benefit and some increased near
benefit.
The increase in tropicamide concentration from 0.042% w/v (formulas
#8-#11) to 0.044% w/v (formulas #13-#18) resulted in a decrease in
ache to negligible amounts. The amount of ache may also be
correlated with the age of the individual. For those individuals
under the age of 45, an increase of tropicamide concentration to a
range from 0.046% to 0.060% w/v may be preferred.
Further, Table 6 shows an unexpected result seen in formulas #13
and #17 where the increase of NaCl from 0.25% w/v to a range of
0.50 to 0.75% w/v resulted in an acceptable redness score of only
1.0 even without the addition of the redness reducing agent
brimonidine.
Formulas #15, #16 and #17 each result in an overall maximum rating
of 5 by combining the benefits of: (1) reduced aceclidine
concentrations to improve the amount of light produced without
significantly affecting the near vision benefits seen in formulas
#8-#12; (2) increased NaCl concentrations resulting in a further
reduction in redness even in the absence of brimonidine; and (3)
increased CMC concentrations resulting in longer residency time on
the eye.
Formula #19 is an excellent alternative for the minority of
individuals that are high responders to formulas #15-#17 and get
noticeable dimming with 1.53% w/v aceclidine. Formula #20 is an
excellent alternative for the minority of individuals that are low
responders to formula #19. Lastly, Formula #21 is an excellent
alternative for the minority of individuals that are low responders
and get poor pupil response with Formula #20.
Example 5 Comparison of Effects of Polyoxyl 40 Stearate, HP.beta.CD
and Poloxamer 407
TABLE-US-00007 TABLE 7 Comparison of Effects of Polyoxyl 40
Stearate, HP.beta.CD and Poloxamer 407. #22 #23 #24 Aceclidine
1.45% 1.45% 1.45% Tropicamide 0.044% 0.044% 0.044% Brimonidine
0.040% 0.040% 0.040% Polyoxyl 40 Stearate 5.5% HP.beta.CB 5.5%
Poloxamer 407 5.5% CMC 0.80% 0.80% 0.80% NaCl 0.037% 0.037% 0.037%
EDTA 0.015% 0.015% 0.015% BAK 0.007% 0.007% 0.007% pH 7.00 7.00
7.00 phosphate buffer 5 mM 5 mM 5 mM Nasal Congestion 0.00 0.50
1.50 Stinging 0.25 0.25 0.25 Wetting 4.00 4.00 4.00 Redness 0.25
0.50 0.50 Visual Blur (<15 sec) 0.50 0.50 1.50 Duration 6-8 hrs
6-8 hrs 6-8 hrs Overall 0-4 4.00 4.00 4.00
Clinical Protocol
20 presbyopic patients with full distance correction were each
given one of the above formulas (#22-#23). All patients received
pre- and post-drop distance and near acuity measurement, Zeiss
Visante.RTM. (Visante is a registered trademark of Carl Zeiss
Meditec AG) optical adherence tomography, axial length and contrast
acuity testing (i.e. Colenbrander-Michelson 10% Lum target) with
the following results: all patient achieved a miotic pupil of 1.5
to 2.20 mm; no patient experienced ciliary ache, ciliary spasm, or
induced accommodation; all patients achieved 20/30+ visual acuity
or better at 14'' and were very satisfied with their high contrast
near vision results and there was no significant complaint of
burning or aching; the duration of effect lasted 6-8 hrs in all
cases; binocular vision afforded all patients 1-1.5 additional
lines of near acuity over monocular testing; the last 10 patients
were tested at 20'' (i.e. computer distance, cell phone distance)
and all achieved 20/25 or better near visual acuity; moderately
hyperopic (approx. +2.25 sphere) uncorrected presbyopes were very
satisfied with distance visual acuity that improved to a 20/25 or
better level at distance and near vision in the 20/30 range; and
uncorrected distance acuity was often improved for those patients
who chose not to routinely correct a small refractive error.
As seen in Table 7, the use of polyoxyl 40 stearate provides the
most comfortable aceclidine formulation with the least amount of
visual blur and redness. To achieve similar results to that of
formula #22, formula #23 requires 10-15% higher concentrations of
the non-ionic surfactant and formula #24 requires 15-20% higher
concentrations of the non-ionic surfactant. HP.beta.CD induced a
color change over time, possibly indicative of oxidation.
Captisol.RTM. (sulfobutylether .beta.-cyclodextrin) was substituted
with similar findings.
Example 6 Modulation of Aceclidine Concentrations in a Preferred
Embodiment
Preferred embodiment: Aceclidine 1.35%-1.55% w/v; Polyoxyl 40
stearate 5.5% w/v; NaCl 0.037% w/v; a viscosity agent, preferably
CMC 0.80% w/v or an amount of Carbopol 934 or 940 sufficient to
achieve a viscosity of from about 5 to about 35 cps upon topical
instillation, such as Carbopol.RTM. 940 at a concentration from
about 0.09% to about 1.0% w/v; BAK 0.015% w/v; and a phosphate,
citrate, citrophosphate, or acetate buffer from about 3 to about 10
mM, wherein the pH is from about 4.75 to about 6.0.
For 1.35% w/v aceclidine--
Stinging on topical instillation 0.25/4.0 (lasting about 2-5
seconds);
Induced redness at 10 minutes: 1.0 to 1.5/4.0;
Induced redness at 30 minutes: 0.0 to 0.25/4.0;
Comfort: very high.
Wetting: very high, the eye maintaining sensation of improved
wetting for most of a 24-hour period after a single topical
instillation.
Depth of Focus distance: excellent.
Depth of Focus near: excellent.
In testing the above formulations on several subjects, it was
discovered that there is a slight range in clinical effect
depending on the concentration of aceclidine, where 1.35%-1.55% w/v
aceclidine is preferred, but for which 1.35% w/v and 1.45% w/v
confer the desired benefits on most subjects.
Further, it is discovered that the clinical effect of 1.35% w/v
aceclidine can be improved when instilled as follows: 1) baseline
effect: 1 drop to each eye. 2) enhanced effect: 2 drops to each
eye. 3) greater effect: after 2) above repeat 1) above. 4) maximum
effect: after 2) above repeat 2) above.
Example 7 Use of a Preferred Embodiment to Prolong Contact Lens
Wear
Preferred embodiment: Aceclidine 1.45% w/v; Polyoxyl 40 stearate
5.5% w/v; NaCl 0.037% w/v; a viscosity agent, preferably CMC 0.80%
w/v or an amount of Carbopol.RTM. 934 or 940 sufficient to achieve
a viscosity of from about 5 to about 35 cps upon topical
instillation, such as Carbopol.RTM. 940 at a concentration from
about 0.09% to about 1.0% w/v; BAK 0.02% w/v; and a phosphate,
citrate, citrophosphate, or acetate buffer from about 3 to about 10
mM, wherein the pH is from about 4.75 to about 6.0.
As a baseline, the subject, who normally wore extended wear lenses
(Air Optix.RTM.; Air Optix is a registered trademark of Novartis
AG) for daily wear only, slept in these lenses overnight. On
arising each morning, the subject's vision was blurred, and the
contact lenses required removal and cleaning of film and deposits
that had formed overnight. Average vision on arising at distance:
20.60; average vision at near on a Michelson contrast acuity chart:
20.80.
Then, for seven consecutive days the above formulation was
instilled between 7 am and 10 am each day as a single dose. Subject
wore the Air Optix.RTM. lenses throughout each day and slept in the
lenses overnight. Upon arising each morning, the subject's vision
at distance: 20.20+; vision at near 20.40 unaided (consistent with
subject's baseline presbyopia when the subject did not wear the
lenses overnight and instead inserted the lenses upon arising).
Example 8 Comparison of Effects of Polyoxyl 40 Stearate and
Captisol.RTM. (Sulfobutylether .beta.-Cyclodextrin
TABLE-US-00008 TABLE 8 Comparison of Effects of Polyoxyl 40
Stearate and Captisol .RTM. (sulfobutylether .beta.-cyclodextrin).
#25 #26 #27 #28 #29 #30 #31 #32 #33 Aceclidine 1.35% 1.35% 1.35%
1.35% 1.35% 1.35% 1.35% 1.35% 1.35% Tropicamide 0.044% 0.044%
0.044% 0.044% 0.044% 0.044% 0.044% 0.044% 0.044%- Polyoxyl 40 5.5%
5.5% 5.5% 5.5% 5.5% 5.5% 5.5% stearate Captisol .RTM. 5.5% 5.5%
Cocamidopropyl 0.10% betaine EDTA 0.015% 0.015% 0.005% 0.005%
0.005% 0.005% 0.015% CMC 1% = 0.80% 0.80% 0.80% 0.80% 0.80% 0.80%
0.80% 0.80% 0.80% 2,500 cps NaCl 0.037% 0.037% 0.037% 0.037% 0.037%
0.037% 0.037% 0.037% 0.037% Mannitol 4% 4% BAK 0.007% 0.007% 0.007%
0.007% 0.007% 0.007% 0.007% 0.007% 0.007% Borate buffer 4 4 4 4 4 4
4 (mM) Phosphate 4 4 buffer (mM) pH 7 7 7 7 7 7 7 7 7 Redness, 10
min 1.25 1.25 2 2 1.75 1.75 0 0 0 Redness, 30 min 0 0 1.5 1.5 1.25
1.25 0 0 0 Pupil, 30 min <2 <2 <2 <2 <2 <2 <2
<2 <3 (mm) Blur on instill 10 10 10 10 10 10 10 10 10 (sec)
Ache 0 0 0 0 0 0 1 0 0 Rating 4.00 4.00 2.00 2.00 2.50 2.50 1.00
5.00 TBD
As seen in Table 8, when using polyoxyl 40 stearate as the
surfactant the exclusion of EDTA results in reduced redness and
best overall rating among polyoxyl 40 stearate compositions
(Formulas #25 and #26). The addition of cocamidopropyl betaine
("CAPB") further reduces redness however results in significant
ache (Formula #31). Replacing polyoxyl 40 stearate with
Captisol.RTM. (sulfobutylether(.beta.-cyclodextrin) and adding
mannitol achieves similar results in redness reduction as the
addition of CAPB to polyoxyl 40 stearate but without the attendant
ache resulting in the highest overall rating among aceclidine
compositions (Formula #32). After several weeks formulations with
Captisol.RTM. (sulfobutylether .beta.-cyclodextrin) had an orange
hue, possibly indicative of oxidation.
Example 9 Preferred Cold Chain Composition
Composition aceclidine at a concentration of about 1.40%-1.80% w/v;
and tropicamide at about 0.42% w/v; polyoxyl 40 stearate at about
5.5% w/v; mannitol at a concentration of about 2.5% to 4.5% w/v;
carbomer 940 at a concentration of about 0.09% to about 2.0% w/v;
optionally, a preservative such as BAK at a concentration of about
0.2% w/v; optionally citrate at a concentration of about 0.1%;
optionally with acetate or phosphate buffer at 2-100 mM, more
preferably 3-5 mM wherein said composition has a pH of about 4.50
to about 5.0; and preferably, about 4.75 to about 5.0; and wherein
w/v denotes weight by volume
A composition as described above was administered to a 62-year-old
subject. It resulted in pupils of 1.8-1.9 mm ou, 20.20+reading
vision, and 20.20+distance vision; whereas without carbomer 940
reduced effectiveness resulted at 2.5% mannitol, and no near vision
effect resulted at 4.0% mannitol. No ciliary spasm or loss of
distance vision resulted. Onset was within about 15 minutes.
Transient redness of about 1+/out of 4 was noted for about 20
minutes without alpha agonist vasoconstrictor. The presence or
absence of BAK had no clinical effect, and was used to provide an
optional preservative.
Example 10 Stabile Aceclidine Formulations
Composition Tested: aceclidine at a concentration of about 1.50%
w/v; tropicamide at a concentration of about 0.042% w/v; polyoxyl
40 stearate at a concentration of about 5.5% w/v; mannitol at a
concentration of about 2.5% w/v; citrate at a concentration of
about 3 mM; wherein said composition has a pH of about 4.75.
20 samples of the above composition were divided evenly and stored
at 25.degree. C. and 4.degree. C. Prior to storage, initial
concentrations of aceclidine were measured using high-pass liquid
chromatography ("HPLC"). The amount of aceclidine in each solution
was calculated by the area under the principal peak compared to a
reference solution of aceclidine. Samples were then subject to
storage for 3 months. Aceclidine measurements were taken at 1, 2
and 3 months. Results of the stability test are shown in Table
9.
TABLE-US-00009 TABLE 9 Stability of Aceclidine in Cold Chain
Storage 25.degree. C. 4.degree. C. Initial 100% 100% 1 month 92%
93% 2 months 75% 92% 3 months 50% 88%
As seen in Table 9 "cold chain storage" or storage of the
aceclidine composition at from 2.degree. C. to 8.degree. C.
resulted in a significant increase in stability of aceclidine at
all 3 time points.
Example 11 Use of Compositions Containing Little or No Cycloplegic
Agent
Aceclidine alone causes incidence migraine-like severe ciliary
spasm (brow ache) and myopic blur. These effects are inversely
correlated to age with subjects age 40 reporting the highest
incidence and subject age 60+reporting the lowest incidence. The
addition of a cycloplegic agent reduces ciliary spasms and
attendant brow ache, migranious headache, squeezing pressure around
eyes or other symptoms of ciliary spasms. The addition of the
cycloplegic agent, surprisingly, does not reduce the myopic effect
of aceclidine. The addition of 2.5% w/v mannitol however does
reduce the myopic effect of aceclidine. Increasing the aceclidine
concentration overcomes this reduction in myopic effect seen with
the addition of mannitol. Surprisingly, however, the increase in
aceclidine is not coincident with an increase in ciliary spasm.
Even more surprising, the concentration of the cycloplegic agent
can be reduced or even eliminated in the presence of mannitol
without an increase in ciliary spasm. Thus, combining a higher
concentration of aceclidine with little to no cycloplegic agent in
the presence of mannitol results in an improvement of near vision
acuity without attendant side effects on par with lower
concentrations of aceclidine and higher concentrations of the
cycloplegic agent in the absence of a cycloplegic agent.
Further and unexpectedly, the addition of a nonionic surfactant
increases both the quantitative measure of near vision improvement
and the duration. This effect is concentration sensitive. In a
preferred embodiment the non-ionic surfactant is at least 1%,
preferably at least 2%, more preferably from about 1% to about 5%,
and most preferably about 5%. For example, polysorbate 80 or
polyoxyl 40 stearate at a concentration from about 1% to about 5%
w/v results in about 1.5 to about 2.0 lines of improvement and a
duration from about 4 to about 5 hours.
Not to be held to particular theory, the increase in concentration
of a surfactant may crowd the surface of the cornea, and at an
optimal concentration this crowding result in small and probably
nanometer diameters, which given the dual polarity of surfactants,
where nonionic are most preferred, enhances corneal absorption of
the entrapped highly polar aceclidine molecules.
The further addition of a viscosity agent by itself does not
enhance duration. Surprisingly, the addition of a viscosity agent
in a formulation with optimal ratios of aceclidine, tropicamide and
a non-ionic surfactant dramatically improves duration. For example,
a formulation of the present invention comprising 1.75% aceclidine,
2.5% mannitol, 0.01% tropicamide, 5% polysorbate 80 improves near
vision in a presbyopic patient by up to 3 lines of vision acuity
for about 4 to about 5 hours. The addition of 1.4% CMC further
increases the near vision improvement to from about 7 to about 10
hours. Not to be held to a particular theory, a threshold above the
critical micellar threshold greatly enhances permeation through the
cornea by reducing micelle size from micrometers to nanometers. See
FIG. 2.
Examples of compositions containing little or no cycloplegic agent
are shown in Table 10 below.
TABLE-US-00010 TABLE 10 Compositions containing little or no
cycloplegic agent #L1 #L2 #L3 #L4 #L5 #L6 #L7 #L8 Aceclidine 1.75%
1.75% 1.75% 1.75% 1.75% 1.75% 1.75%.sup. 1.75%.sup. Tropicamide
0.02% 0.02% 0.02% 0.02% 0.02% -- -- -- Mannitol 2.5% 2.5% 2.5% 2.5%
2.5% 2.5% 2.5%.sup. 2.5%.sup. Polysorbate 80 0.75% 0.25% 0.25% 0.1%
0.1% 0.5%.sup.# 0.25%.sup. 0.25%.sup. Carbopol .RTM. 940 0.95%
0.95% 0.95% 0.9% 0.95% 0.95%* 0.95%* 0.95%* or CMC Glycerine
Phosphate buffer 3 mM -- 3 mM 3 mM 3 mM 3 mM -- 3 m M NaCl 0.5%
0.1% 0.05% -- 0.1% 0.5%.sup.# 0.1%.sup. 0.05%.sup. Boric acid --
0.12% 0.2% 0.2% 0.12% -- 0.12%.sup. 0.2%.sup. BAK 0.015% 0.01%
0.01% 0.05% 0.01% 0.015%.sup. 0.01%.sup. 0.01%.sup. pH 5.0 5.0 5.0
5.0 5.0 5.0 5.0 5.0 #L9 #L10 #L11 #L12 #L13 #L14 #L15 #L16
Aceclidine 1.75%.sup. 1.75%.sup. 1.65% 1.65% 1.75% 1.75% 1.65%
1.75% Tropicamide -- -- 0.01% -- -- 0.025% 0.025% 0.025% Mannitol
2.5%.sup. 2.5%.sup. 2.5% 2.5% 2.5% 2.5% 2.5% 2.5% Polysorbate 80
0.1%.sup. 0.1%.sup. 2% 2% 1% 0.10% 2.50% 2.50% Carbopol .RTM. 940
0.9%* 0.95%* 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% or CMC Glycerine
0.10% 0.10% 0.10% 0.10% 0.10% 0.10% Phosphate buffer 3 mM 3 mM 3 mM
3 mM 3 mM 3 mM 3 mM 3 mM NaCl -- 0.1%.sup. -- -- -- -- -- -- Boric
acid 0.2%.sup. 0.12%.sup. -- -- -- -- -- -- BAK 0.05%.sup.
0.01%.sup. 0.01% 0.01% 0.01% 0.01% 0.015% 0.015% pH 5.0 5.0 5.0 5.0
5.0 5.0 5.25 5.25 #L17 #L18 #L19 #L20 #L21 Aceclidine 1.75% 1.75%
1.75% 1.75% 1.75% Tropicamide 0.025% 0.025% 0.025% 0.015% 0.015%
Mannitol 2.5% 2.5% 2.5% 2.5% 2.5% Polysorbate 80 3.00% 2.50% 2.50%
2.50% 2.50% Carbopol .RTM. 940 0.75% 1.50% 0.75% 0.75% 0.75% or CMC
Glycerine 0.10% 0.10% 0.20% 0.20% 0.20% Phosphate buffer 3 mM 3 mM
3 mM 3 mM 3 mM NaCl -- -- -- -- -- Boric acid -- -- -- -- -- BAK
0.015% 0.015% 0.015% 0.015% 0.015% pH 5.25 5.25 5.25 5.25 5.25 #L22
#L23 #L24 #L25 #L26 #L27 #L28 #L29 Aceclidine 1.65% 1.75% 1.75%
1.75% 1.75% 1.65% 1.75% 1.75% Tropicamide 0.025% 0.275% 0.020%
0.015% 0.027% 0.0275% 0.0275% 0.0275% Mannitol 2.5% 2.5% 2.5% 2.5%
2.5% 2.5% 2.5% 2.5% Polysorbate 80 5% 5% 5% 5% 5% 5% 5% 5% Carbopol
.RTM. 940 1.25% 1.45% 1.45% 1.45% 1.45% 1.25% 1.40% 1.40% or CMC
Glycerine Phosphate buffer 3 mM 3 mM 3 mM 3 mM 3 mM 3 mM 3 mM 3 mM
NaCl -- -- -- -- -- -- -- -- Boric acid -- -- -- -- -- -- -- -- BAK
0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% pH 5.0 5.0 5.0 5.0
6.0 5.0 5.0 5.0 Pupil Size (mm) Reading vs. 3+ 3+ 3+ 3+ 3+ 3+ 3+ 3+
Baseline 40 cm Duration (hours) 7 10+ 10+ 10+ 10+ 7.0 10+ 10+
Ciliary Spasms 0.0 tr 0.5 1.0 1.0 0.0 tr 0.5 Stinging 0.5 0.5 0.5
0.5 0.5 0.5 0.5 0.5 Blur (min) 1 1 1 1 1 1 1 1 Distance Blur Onset
(min) 20 20 20 20 20 20 20 20 Redness 1 hr (0-4) 0.5 0.5 0.5 0.5
0.5 0.5 0.5 0.5 Redness 4 hr (0-4) Overall Comfort sl sticky sl
sticky sl sticky sl sticky sl sticky sl sticky sl sticky sl sticky
Osmolarity Efficacy index: read*dur OVERALL (1-5) best best best
best best best best best #L30 #L31 #L32 Aceclidine 1.75% 1.75%
1.75% Tropicamide 0.025% 0.022% 0.0175% Mannitol 2.5% 2.5% 2.5%
Polysorbate 80 5% 5% 5% Carbopol .RTM. 940 1.50% 1.40% 1.50% or CMC
Glycerine Phosphate buffer 3 mM 3 mM 3 mM NaCl -- -- -- Boric acid
-- -- -- BAK 0.01% 0.01% 0.01% pH 5.0 5.0 6.0 Pupil Size (mm)
Reading vs. 3+ Baseline 40 cm Duration (hours) 10+ Ciliary Spasms
1.0 1.0 Stinging 0.5 Blur (min) 1 Distance Blur Onset (min) 20
Redness 1 hr (0-4) 0.5 Redness 4 hr (0-4) Overall Comfort sl sticky
Osmolarity Efficacy index: read*dur OVERALL (1-5) best #L33 #L34
#L35 #L36 #L37 #L38 #L47 #L48 Aceclidine 1.75% 1.40% 1.40% 1.25%
1.45% 1.45% 1.45% 1.55% Tropicamide -- -- -- -- -- 0.0200% --
0.0200% Brimonidine -- -- -- -- -- -- -- -- Mannitol -- -- -- -- --
-- 2.5% 4.0% Polysorbate 80 -- -- -- -- -- -- -- -- Polyoxyl 40
Stearate -- -- -- -- 5.5% 5.5% 5.5% 5.5% Citrate 0.10% 0.10% 0.10%
0.10% 0.10% 0.10% 0.10% 0.10% Glycerine -- 0.10% 0.10% 0.10% 0.10%
0.10% 0.10% 0.10% CMC -- 1.45% 0.75% -- 0.85% 0.75% 0.75% 0.75%
HPMC -- -- -- -- -- -- -- -- Carbopol .RTM. 940 -- -- -- -- -- --
-- -- NaCl 0.75% 0.75% 0.50% 0.50% 0.50% 0.50% 0.50% 0.50% Boric
Acid -- -- -- -- -- -- -- -- Postassium Borate -- -- -- -- -- -- --
-- Phosphate buffer 3 3 3 3 3 3 3 3 Acetate -- -- -- -- -- -- -- --
pH 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 BAK 0.015% 0.015% 0.015% 0.015%
0.015% 0.015% 0.015% 0.015% Pupil Size (mm) Reading vs. 3 3.25 3 2
3 2.5 1.5 0.5 Baseline 40 cm Duration (hours) 4 7 4.5 6.5 6 3 2
Ciliary Spasms 4 4 3 2 3 2 0.5 0.5 Stinging 1.0 1.0 1.0 1.0 1 1
Blur (min) Distance blur none none none none none none none none
Onset (min) 20-11 20-12 20-13 20-14 20-15 20-16 20-25 20-25 Redness
1 hr (0-4) 2.0 1.5 0.5 0.5 0.5 0.5 Redness 4 hr (0-4) Overall
comfort poor poor poor fair poor poor good good Osmolarity hi hi hi
hi hi hi hi hi Efficacy index: 12 23 14 0 20 15 5 1 read*dur
OVERALL (1-5) * ** 1/2 * -- * ** *** * #L49 #L50 #L51 #L52 #L53
#L54 #L55 #L56 Aceclidine 1.65% 1.75% 1.65% 1.65% 1.65% 1.65% 1.75%
1.75% Tropicamide 0.0300% 0.0300% 0.0200% 0.0100% 0.0250% 0.0000%
0.0000% 0.0250- % Brimonidine -- -- -- -- -- -- -- -- Mannitol 2.5%
2.5% 2.5% 2.5% 2.5% 2.5% 2.5% 2.5% Polysorbate 80 -- 5.00% -- 2.00%
2.50% 2.00% 1.00% 0.10% Polyoxyl 40 Stearate 5.5% -- 5.5% -- -- --
-- -- Citrate 0.10% -- 0.10% -- 0.10% -- -- -- Glycerine 0.10%
0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% CMC 0.75% 0.75% 0.75%
0.75% 0.85% 0.85% 0.85% 0.85% HPMC -- -- -- -- -- -- -- -- Carbopol
.RTM. 940 -- -- -- -- -- -- -- -- NaCl 0.50% 0.50% 0.00% 0.50%
0.50% -- -- -- Boric Acid -- -- -- -- -- -- -- -- Postassium Borate
-- -- -- -- -- -- -- -- Phosphate buffer 3 3 3 3 3 3 3 3 Acetate --
-- -- -- -- -- -- -- pH 5.25 5.0 5.0 5.0 5.0 5.0 5.3 5.3 BAK 0.015%
0.015% 0.015% 0.015% 0.015% 0.015% 0.015% 0.015% Pupil Size (mm)
Reading vs. 1.5 1.5 1 2.5 3 3 2 1.5 Baseline 40 cm Duration (hours)
4 4 2 6 5 6 4 4 Ciliary Spasms 0.5 0.5 0.5 0.5 0.5 2 2 0 Stinging
0.5 1 1 1 0.5 1 0.5 0.5 Blur (min) Distance blur none none none
none none none none none Onset (min) 20-25 20-25 20-25 20-25 20-25
20-25 20-25 20-25 Redness 1 hr (0-4) 0.5 0.5 0.5 0.5 0.5 0.5 0.5
1.0 Redness 4 hr (0-4) Overall comfort good good good poor poor
poor poor good Osmolarity hi hi hi hi hi nl nl nl Efficacy index: 6
6 2 15 15 18 8 6 read*dur OVERALL (1-5) * * * ** #L57 #L58 #L59
#L60 #L61 #L62 #L63 #L64 Aceclidine 1.65% 1.65% 1.65% 1.65% 1.65%
1.75% 1.65% 1.75% Tropicamide 0.0250% 0.0250% 0.0150% 0.0400%
0.0250% 0.0300% 0.0250% 0.0250- % Brimonidine -- -- -- -- -- -- --
-- Mannitol 2.5% 2.5% 2.5% 2.5% 2.5% 2.5% 2.5% 2.5% Polysorbate 80
2.00% 2.50% 2.50% 3.50% 2.50% 3.50% 2.50% 3.50% Polyoxyl 40
Stearate -- -- -- -- -- -- -- -- Citrate -- -- -- -- -- -- -- --
Glycerine 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% CMC 0.85%
0.85% 0.75% 0.60% 1.60% 0.60% 0.75% 0.50% HPMC -- -- -- -- -- -- --
-- Carbopol .RTM. 940 -- -- 0.75% 0.60% 0.60% 0.50% NaCl -- -- --
-- -- -- -- -- Boric Acid -- -- -- -- -- -- -- -- Postassium Borate
-- -- -- -- -- -- -- -- Phosphate buffer 3 3 3 3 3 3 3 3 Acetate --
-- -- -- -- -- pH 5.3 5.00 5.00 5.00 5.00 5.00 5.00 5.00 BAK 0.015%
0.015% 0.015% 0.015% 0.015% 0.015% 0.015% 0.015% Pupil Size (mm)
Reading vs. 2.5 3 2 1.5 2.5 2.5 2 2.5 Baseline 40 cm Duration
(hours) 6 5.5 7 3 7 7 4 Ciliary Spasms 0 0 0.5 0 0.5 0.5 0.5 0.5
Stinging 0.5 0.5 0.5 0.25 0.25 0.25 0.5 0.5 Blur (min) 1.5 1 2
Distance blur none none none none none none none none Onset (min)
20-25 20-25 20-25 20-25 20-25 20-25 20-25 20-25 Redness 1 hr (0-4)
0.5 0.5 0.5 0.5 0.5 0.5 0.5 Redness 4 hr (0-4) Overall comfort good
good good good good good good good Osmolarity nl nl nl nl nl nl nl
nl Efficacy index: 15 17 14 5 18 18 8 0 read*dur OVERALL (1-5) ****
**** poor #L65 #L66 #L67 #L68 #L69 #L70 #L71 #L72 Aceclidine 1.65%
1.75% 1.75% 1.75% 1.75% 1.75% 1.75% 1.75% Tropicamide 0.0250%
0.0275% 0.0275% 0.0275% 0.0250% 0.0180% 0.0160% 0.0160- %
Brimonidine -- -- -- -- -- -- -- -- Mannitol 2.5% 2.5% 2.5% 2.5%
2.5% 2.5% 2.5% 2.5% Polysorbate 80 4.00% 5.00% 5.00% 2.00% 2.00%
2.00% 2.25% 4.00% Polyoxyl 40 Stearate -- -- -- -- -- -- -- --
Citrate -- -- -- -- -- -- -- -- Glycerine 0.10% -- -- -- -- -- --
-- CMC 0.75% -- 1.35% 1.35% 1.45% 1.45% 1.45% HPMC -- -- -- -- --
-- -- -- Carbopol .RTM. 940 1.35% -- 1.45% -- -- -- -- NaCl -- --
-- -- -- -- -- -- Boric Acid -- -- -- -- -- -- -- -- Postassium
Borate -- -- -- -- -- -- -- -- Phosphate buffer 3 3 3 3 3 3 3 3
Acetate -- -- -- -- -- -- -- pH 5.00 5.0 5.0 5.0 5.0 5.0 5.0 5.0
BAK 0.015% 0.015% 0.015% 0.015% 0.015% 0.015% 0.01% 0.01%
Pupil Size (mm) Reading vs. 2 2.75 2.75 2.75 2.75 2.75 2.75 2.75
Baseline 40 cm Duration (hours) 5 7 7 5.5 6 7 7 7 Ciliary Spasms
0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Stinging 0.5 0.5 0.5 0.5 Blur (min)
1 Distance blur none none none none none none none none Onset (min)
20-25 20-25 20-25 20-25 20-25 20-25 20-25 20-25 Redness 1 hr (0-4)
0.5 0.5 0.5 0.5 Redness 4 hr (0-4) Overall comfort good good good
good good good good good Osmolarity nl nl nl nl nl nl nl nl
Efficacy index: 10 19 19 15 17 19 19 19 read*dur OVERALL (1-5) ? **
1/2 ** **** #L73 #L74 #L75 #L76 #L77 #L78 #L79 #L80 Aceclidine
1.75% 1.75% 1.75% 1.75% 1.75% 1.75% 1.75% 1.75% Tropicamide 0.0150%
0.0150% 0.0150% 0.0120% 0.0110% 0.0100% 0.0000% -- Brimonidine --
-- -- -- -- -- 0.015% -- Mannitol 2.5% 2.5% 2.5% 2.5% 2.5% 2.5%
2.5% 2.5% Polysorbate 80 4.00% 5.00% 5.00% 5.00% 5.00% 5.00% 5.00%
-- Polyoxyl 40 Stearate -- -- -- -- -- -- -- -- Citrate -- -- -- --
-- -- -- -- Glycerine -- -- -- -- -- -- -- -- CMC 1.45% 1.45% 1.43%
1.43% 1.40% 1.40% 1.40% 1.40% HPMC -- -- -- -- -- -- -- -- Carbopol
.RTM. 940 -- -- -- -- -- -- -- -- NaCl -- -- -- -- -- -- -- --
Boric Acid -- -- -- -- -- -- -- -- Postassium Borate -- -- -- -- --
-- -- -- Phosphate buffer 3 3 3 3 3 3 3 3 Acetate -- -- -- -- -- --
-- -- pH 5.0 5.0 5.0 5.0 5.0 5.0 5.0 BAK 0.01% 0.01% 0.01% 0.01%
0.01% 0.01% 0.01% -- Pupil Size (mm) Reading vs. 3 3.25 3.25 3.5
3.5 3.75 2.5 2.5 Baseline 40 cm Duration (hours) 7.5 7.5 7.5 7 8 9
8 7 Ciliary Spasms 0.5 0.5 0.5 1 1 1 2 2 Stinging Blur (min) 1.5
1.5 1.5 Distance blur none none none none none none none none Onset
(min) 20-25 20-25 20-25 20-25 20-25 20-25 20-25 20-25 Redness 1 hr
(0-4) Redness 4 hr (0-4) Overall comfort good good-exc good-exc
good-exc exc exc fair fair Osmolarity nl nl nl nl nl nl nl nl
Efficacy index: 23 24 24 25 28 34 20 18 read*dur OVERALL (1-5) ****
1/2 ***** ***** *****! *****!! *****!! **** **** #L81 #L82 #L83
#L84 #L85 #L86 #L87 #L88 Aceclidine 1.75% 1.75% 1.65% 1.40% 1.75%
1.75% 1.75% 1.75% Tropicamide 0.0100% 0.0150% 0.0000% 0.0000%
0.0000% 0.0100% 0.0900% 0.0060- % Brimonidine -- -- -- -- -- -- --
-- Mannitol 2.5% 2.5% 2.5% 2.5% 2.5% 2.5% 2.5% 2.5% Polysorbate 80
6.00% 7.00% 0.00% 0.00% 5.00% 2.5% 2.5% 2.5% Polyoxyl 40 Stearate
-- -- -- 5.5% -- -- -- -- Citrate -- -- -- -- -- -- -- -- Glycerine
-- -- -- -- -- -- -- -- CMC 1.40% 1.40% 0.00% 0.75% 1.40% -- -- --
HPMC -- -- -- -- -- 1.75% 1.75% 1.75% Carbopol .RTM. 940 -- -- --
-- -- -- -- -- NaCl -- 0.50% -- -- 0.00% 0.50% -- 0.50% Boric Acid
-- -- -- -- -- -- 0.35% -- Postassium Borate -- -- -- -- -- --
0.47% -- Phosphate buffer 3 3 3 3 3 3 3 3 Acetate -- -- -- -- -- --
-- -- pH 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 BAK 0.01% 0.01% 0.010%
0.010% 0.010% 0.020% 0.020% 0.020% Pupil Size (mm) Reading vs. 2.75
2.5 1 1.5 3.5 3.5 3.5 3.75 Baseline 40 cm Duration (hours) 5.5 5 3
3.5 7 8 7 9 Ciliary Spasms 0.5 0.5 1 1 2 0.5 0.5 0.5 Stinging 1.0
0.5 Blur (min) Distance blur none none none none 2.0 none none none
Onset (min) 20-25 20-25 20-25 20-25 20-25 20-25 20-25 20-25 Redness
1 hr (0-4) 2.0 1.0 1.0 0.5 0.5 Redness 4 hr (0-4) Overall comfort
good good fair good good good good Osmolarity nl hi nl nl nl nl nl
nl Efficacy index: 15 13 3 5 25 28 25 34 read*dur OVERALL (1-5) ***
*** * **** #L89 #L90 #L91 #L92 #L93 #L94 Aceclidine 1.75% 1.75%
1.75% 1.75% 1.75% 1.75% Tropicamide 0.0060% 0.0100% 0.0060% 0.0060%
0.0060% 0.0060% Brimonidine -- -- -- -- -- -- Mannitol 2.5% 2.5%
2.5% 2.5% -- 2.5% Polysorbate 80 2.5% 2.50% 2.50% 2.75% 2.75% 3.50%
Polyoxyl 40 Stearate -- -- -- -- -- -- Citrate -- -- -- -- -- --
Glycerine -- -- -- -- -- -- CMC -- -- -- -- -- -- HPMC 1.75% -- --
-- -- -- Carbopol .RTM. 940 -- 1.75% 1.75% 1.80% 1.80% 1.80% NaCl
-- 0.50% 0.50% 0.50% 0.50% 0.50% Boric Acid -- -- -- -- 0.25% --
Postassium Borate -- -- -- -- 0.37% -- Phosphate buffer 4 3 3 3 3 3
Acetate -- -- -- pH 6.0 5.0 5.0 5.0 5.0 5.0 BAK 0.020% 0.02% 0.02%
0.02% 0.02% 0.02% Pupil Size (mm) Reading vs. 3.75 3.5 3.75 3.75
3.75 3.75 Baseline 40 cm Duration (hours) 9 7 7 8 8 8.5 Ciliary
Spasms 0.5 0.5 0.5 0 0 0 Stinging Blur (min) Distance blur none
none none none none none Onset (min) 20-25 20-25 20-25 20-25 20-25
20-25 Redness 1 hr (0-4) 0.5 0.5 0.5 0.5 0.5 0.5 Redness 4 hr (0-4)
Overall comfort good Osmolarity lo Efficacy index: 34 25 26 30 30
32 read*dur OVERALL (1-5) ***** ***** ***** ***** ***** All
concentration in weight by volume. mm denotes millimeters. cm
denotes centimeters. min denotes minutes. %* denotes amount can
optionally vary from about 0.01% to about 1% w/v. # denotes
formulation can include polysorbate 80 or not include polysorbate
80. Ciliary spasms scores correspond to the following: 0 = no
discomfort; 0.5 = slight sting; 1 = noticeable squeeze/discomfort;
2 = pain for less than 30 minutes; 3 = pain for 1 hour or more; and
4 = severe to intolerable pain.
The efficacy index is demonstrated in FIG. 3. In brief, the score
is calculated by multiplying the lines of improvement in near
visual acuity by the number of hours the improvement lasts. For
example, a score of: 5 is equal to +1 lines of improvement in near
visual acuity for 5 hours; 10 is equal to +1.5 lines of improvement
for 6.7 hours; 15 is equal to 2 lines of improvement for 7.5 hours;
20 is equal to 2.5 lines of improvement for 8 hours; 25 is equal to
3+ lines of improvement for 8.3 hours and 35 is equal to 3.75+
lines of improvement for 9 hours.
As demonstrated by comparing the Reading vs. Baseline at 40 cm and
Efficacy Indexes of formulas #L33-#L37, formulas containing 1.40%
or more aceclidine are better at correcting presbyopia than those
formulas containing 1.25% aceclidine. Inversely, the lower
concentration of aceclidine results in better overall comfort to
the user. The addition of 2.5% mannitol to formulas with 1.45%
aceclidine improves overall comfort but at the expense of reducing
the presbyopic correcting effect (compare #L37 with #L47.) This
reduction in near vision improvement is exacerbated with the
addition of 4.0% mannitol (compare #L47 with #L48.) Increasing
aceclidine concentrations to 1.65% or 1.75% overcome the reduction
in near vision improvement seen with the addition of mannitol
(compare #L47 with #L49 and #L50.)
Further, formulas containing 1.75% aceclidine and 2.5% mannitol
have an increased efficacy and duration in treating presbyopia that
is correlated with an increase in polysorbate 80 up to 5.0% and
then inversely correlated with a decrease in CMC from 1.45% to
1.40% (compare formulas #L66 to #L78.) Optimal formulations are
demonstrated by #L77, #L78 and #L85-#L94, which each have the
highest improve reading at 40 cm at between 3.5 and 3.75 visual
acuity lines and the highest Efficacy Index scores of 25 to 34, and
the longest duration from 7 to 9 hours. The increase in
effectiveness and duration of formulas from #L66 to #L78 are also
inversely correlated with a decrease in tropicamide from 0.0275% to
0.01%. This same trend is demonstrated by the increase in
effectiveness (i.e. Reading vs. Baseline 40 cm) when comparing #L85
through #L94.
This data demonstrates that mannitol can effectively reduce ciliary
spasms caused by aceclidine, thus reducing the need for a
cycloplegic agent such as tropicamide. Further, this data
demonstrates that the addition of a non-ionic surfactant and
viscosity agent can further enhance the efficacy and duration of
compositions containing aceclidine, mannitol and low tropicamide.
This data also demonstrates that the use of a cycloplegic agent in
aceclidine compositions containing polysorbate 80 and CMC is most
beneficial to presbyopic correction when the cycloplegic agent is
closer to 0.006% than 0.025%. Finally, this data demonstrates that
compositions comprising aceclidine and mannitol are sufficient to
correct presbyopia with tolerable pain.
Example 12 Use of Further High Tropicamide Formulations
The following examples are of aceclidine formulations containing
more than 0.03% tropicamide.
TABLE-US-00011 TABLE 11 High tropicamide formulations #L39 #L40
#L41 #L42 #L43 #L44 #L45 #L46 Aceclidine 1.45% 1.45% 1.40% 1.40%
1.40% 1.40% 1.40% 1.40% Tropicamide 0.035% 0.037% 0.040% 0.050%
0.055% 0.06% 0.08% 0.04% Polyoxyl 40 5.5% 5.5% 5.5% 5.5% 5.5% 5.5%
5.5% 5.5% Stearate Citrate 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%
0.10% 0.10% Glycerine 0.10% 0.10% 0.10% 0.10% 0.10% 0.10% 0.10%
0.10% CMC 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% 0.75% NaCl
0.50% 0.50% 0.50% 0.50% 0.50% 0.50% 0.50% 0.50% Phosphate buffer 3
3 3 3 3 3 3 3 pH 5.0 5.0 5.0 5.25 5.5 5.25 5.0 5.0 BAK 0.015%
0.015% 0.015% 0.015% 0.015% 0.015% 0.015% 0.015% Reading vs. 3.5
3.5 3.5 2 1 1 1 3 Baseline 40 cm Duration (hours) 6 6 6 2 2 1 1 6
Ciliary Spasm 1 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Stinging 1.0 1.0 1.0
0.5 0.25 0.5 1 1 Distance blur none none none none none none none
none Onset (min) 20-17 20-18 20-19 20-20 20-21 20-22 20-23 20-24
Redness 1 hr (0-4) 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Overall comfort
fair good good good good good good good Osmolarity hi hi hi hi hi
hi hi hi Efficacy index: 21 21 21 4 2 1 1 18 read*dur OVERALL (1-5)
** *** *** * 1/2* 1/4* 1/4* *** Ciliary spasms scores correspond to
the following: 0 = no discomfort; 0.5 = slight sting; 1 =
noticeable squeeze/discomfort; 2 = pain for less than 30 minutes; 3
= pain for 1 hour or more; and 4 = severe to intolerable pain.
As demonstrated by formulas #L39-#L41 and compared to formulas
#L74-#L78 in Table 10, formulas containing about 1.40% to about
1.45% aceclidine, about 0.035% to about 0.04% tropicamide, about
5.5% polyoxyl 40 stearate and about 0.75% CMC are almost, but not
quite as effective at treating presbyopia as formulas containing
about 1.65% to about 1.75% aceclidine, about 2.5% mannitol, about
5% polysorbate 80, about 1.40% CMC formulas. This effectiveness
decreases dramatically when tropicamide is increased to about 0.05%
to about 0.08% tropicamide.
Example 13. Use of a Compound Containing Mannitol
Formulation: aceclidine 1.75% w/v tropicamide 0.006% w/v mannitol
2.5% w/v polysorbate 80 2.75% w/v NaCl 0.5% w/v hydroxypropylmethyl
cellulose 0.5%-1.80% w/v phosphate buffer 3 mM pH 5.0, and BAK
0.020% as preservative.
Method:
The subject instilled 2 drops of the above formulation in each eye
and the excess wiped from lids and lashes.
Results:
Within 20 minutes, near vision improvement of about 3 lines of
visual acuity was noted with very slight dimming. Throughout the
day near vision remained enhanced with no loss of distance vision.
Further, if the subject previously suffered from any mild
refractive errors distance vision was improved. Over a 5-8 hour
period the pupil begins to slightly recover, and after a few hours
the minimal dimming was no longer noted. Both excellent near vision
near onset, and possibly still slightly improved near vision
continued as the pupil slightly begins to increase from its minimal
size earlier in the day.
Example 14. Use of a Preferred Embodiment Optimizing Tropicamide
and Hydroxypropyl Methyl Cellulose
Composition
TABLE-US-00012 Aceclidine 1.75% w/v Tropicamide 0.010% w/v Mannitol
2.50% w/v Polysorbate 80 3.50% w/v NaCl 0.50% w/v HPMC 1.25% w/v
BAK 0.02% w/v Phosphate buffer 3 mM pH 5.00
Method
The subject instilled 2 drops of the above formulation in each eye
as 1 single drop each eye and a second drop after 5 minutes.
Results:
Comfort, duration and efficacy were assessed. Stinging upon
instillation and over the first hour was minimal with a score of
0.25 out of 4. Redness over the first hour was also minimal with a
score of 0.5 out of 4 assessed at 20 minutes. Onset of vision
improvement occurred with the first 20 to 25 minutes after
instillation. Baseline near vision (i.e. 40 centimeters) was
improved by 3.5 lines of visual acuity. Improvement in near vision
lasted for 8.5 hours. Comparing this formula to those in Table 10,
the Efficacy Index score was 29.75. Substituting HPMC 1.80% w/v
with HPMC 1.65% w/v resulted in a slight reduction in near vision
improvement to 3.25 lines of visual acuity and a slight reduction
in duration to just over about 6 hour. Comparing this formula to
those in Table 10, the Efficacy Index score was 19.5.
Example 15. Use of a Compound Containing Mannitol with Various
Nonionic Surfactants Compositions
Table 12 lists the active ingredients, excipients and their
concentrations for compositions with both tested and prophetic
examples of nonionic surfactants.
Methods
The subject independently instilled 2 drops of the above
compositions in each eye and the excess wiped from lids and
lashes.
Results
All nonionic surfactants tested demonstrate substantial near vision
improvement. Of those tested only Brij.RTM. 35 was marginal due to
the significant corneal irritation, hyperemia and reduced duration
that resulted. Polysorbate 80 and poly 35 castor oil were most
preferred, polyoxyl 40 stearate and poloxamer 407 excellent as
well. However, polyoxyl 40 stearate caused a precipitate reaction
with cellulose viscosity agents and added other stability
issues.
Comfort and duration for each non-ionic surfactant were also tested
and are noted in Table 12. Stinging and Redness are based on a
scale of 0 to 4 with 0 being none and 4 being the most severe.
Other than Brij.RTM. 35 stinging and redness were mild to nearly
absent. Duration was excellent for each nonionic surfactant
tested.
TABLE-US-00013 TABLE 12 Comparing efficacy and comfort of various
nonionic surfactants Polysorbate Polyoxyl 35 Polyoxyl 40 Poloxamer
Tyloxapol Polysorbate 20 Poloxamer 188 Solulan C-24 % w/v 80 castor
oil stearate 407 Brij .RTM. 35 (prophetic) (prophetic) (prophetic)
(prophetic) Aceclidine 1.75% 1.75% 1.75% 1.75% 1.75% 1.75% 1.75%
1.75% 1.75% Tropicamide 0.006% 0.006% 0.005% 0.005% 0.005% 0.006%
0.006% 0.006% 0.006%- Mannitol 2.5% 2.5% 2.5% 2.5% 2.5% 2.5% 2.5%
2.5% 2.5% Nonionic 3.5% 3.5% 3.5% 3.5% 3.5% 3.5% 3.5% 3.5% 3.5%
surfactant NaCl 0.50% 0.50% 0.50% 0.50% 0.50% 0.50% 0.50% 0.50%
0.50% HPMC 1.80% 1.80% 1.80% 1.80% 1.80% 1.80% 1.80% 1.80% 1.80%
BAK 0.02% 0.02% 0.02% 0.02% 0.02% 0.02% 0.02% 0.02% 0.02% Phosphate
3 mM 3 mM 3 mM 3 mM 3 mM 3 mM 3 mM 3 mM 3 mM buffer pH 5.00 5.00
5.00 5.00 5.00 5.00 5.00 5.00 5.00 Stinging 0.25 0 0.5 0.5 2 0-2
0-2 0-2 0-2 Redness 1 hr 0.5 0.25 0.75 1 2.5 0.25-2.5 0.25-2.5
0.25-2.5 0.25-2.5 Reading vs. 3.75 3.5 3 3 2 2-3.5 2-3.5 2-3.5
2-3.5 Baseline (40 cm) Duration 10 9 7 7 4 4-8 4-8 4-8 4-8 (hours)
Efficacy 37.5 31.5 21 21 8 8-37.5 8-37.5 8-37.5 8-37.5 Index
read*dur Onset (min) 20-25 20-25 20-25 20-25 30-40 20-40 20-40
20-40 20-40
Example 16. Use of a Compound Containing Optimizing Nonionic
Surfactant and Antioxidant Additives and Concentrations
Compositions
TABLE-US-00014 Aceclidine 1.75% w/v Tropicamide 0.010% w/v Mannitol
2.50% w/v Polysorbate 80 4.00% w/v NaCl 0.00% w/v HPMC 1.25% w/v
(high MW equaling viscosity of about 400 cps units) BAK 0.02% w/v
Sorbate 0.12% w/v BAK 0.02% w/v EDTA 0.01% Citrate buffer 3 mM pH
5.00
Method
2 subjects instilled 2 drops each of the above formulation in each
eye about 5 minutes apart.
Results:
Comfort, duration and efficacy were assessed. Stinging upon
instillation and over the first hour was minimal for each subject
with a score of 0.50 out of 4 for about 15 seconds. Redness over
the first hour was also minimal for each subject with a score of
0.25 out of 4 assessed at 20 minutes. Onset of vision improvement
occurred with the first 20 to 25 minutes after instillation. For
subject 1 baseline near vision (i.e. 40 centimeters) was improved
by 4.0-4.25 lines of visual acuity and lasted for 11.5 hours. For
subject 2 baseline near vision was improved by 3.5 lines of visual
acuity and lasted for 9.5 hours. The Efficacy Index score was 47.38
and 33.25, among the highest achieved for any formulation.
Example 17. Aceclidine to Treat Presbyopia
Method
A 1.75% aceclidine in saline solution was formulated. One drop was
instilled into each eye of a presbyopic subject. The visual acuity
of the subject was tested both before and after instillation using
a LogMAR chart.
Results
The subject recorded a best corrected distance visual acuity of
LogMAR 0.50 at 45 centimeters near test card and LogMAR -0.12 best
corrected distance acuity at 1-meter distance prior to
instillation. After instillation the subject recorded a LogMAR
score of 0.22 at 45 centimeters distance and maintained a -0.12
LogMAR score at 1-meter distance. This improved reading distance
acuity was maintained for 3.5 hours post instillation. Noticeable
degradation in reading distance acuity began at 4 hours post
instillation.
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